Systems and methods for ex vivo lung care

ABSTRACT

Methods and systems of maintaining, evaluating, and providing therapy to a lung ex vivo. The methods and systems involve positioning the lung in an ex vivo perfusion circuit; circulating a perfusion fluid through the lung, the fluid entering the lung through a pulmonary artery interface and leaving the lung through a left atrial interface; and ventilating the lung by flowing a ventilation gas through a tracheal interface. Maintaining the lung for extended periods involves causing the lung to rebreath a captive volume of air, and reaching an equilibrium state between the perfusion fluid and the ventilation gas. Evaluating the gas exchange capability of the lung involves deoxygenating the perfusion fluid and measuring a time taken to reoxygenate the perfusion fluid by ventilating the lung with an oxygenation gas.

REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalApplication Ser. No. 61/024,976, filed on Jan. 31, 2008, the entirecontents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The invention generally relates to systems, methods, and devices for exvivo organ care. More particularly, in various embodiments, theinvention relates to a portable device for caring, assessing, andapplying therapeutic measures to a lung or a pair of lungs ex vivo atphysiologic or near-physiologic conditions.

BACKGROUND OF THE INVENTION

Current organ preservation techniques typically involve hypothermicstorage of the organ in a chemical preservation solution on ice. Thesetechniques utilize a variety of solutions, none of which sufficientlyprotect the organ from damage resulting from ischemia. Such injuries areparticularly undesirable when an organ is intended to be transplantedfrom a donor into a recipient.

Effective physiologic preservation of an ex vivo organ would provideimportant benefits compared to conventional approaches. For instance,physiologic ex vivo preservation would permit more careful monitoring,functional testing, assessment, and therapy of the harvested organ. Thiswould in turn allow earlier detection and potential repair of defects inthe harvested organ, further reducing the likelihood of post-transplantorgan failure. The ability to perform and assess simple repairs on theorgan would also allow many organs with minor defects to be saved,whereas current transplantation techniques require them to be discarded.This is of crucial importance when harvesting lungs because lungs areeasily compromised even before harvesting within the donor's body.

In addition, more effective matching between the organ and a particularrecipient may be achieved, further reducing the likelihood of eventualorgan rejection. Current transplantation techniques rely mainly onmatching donor and recipient blood types, which by itself is arelatively unreliable indicator of whether or not the organ will berejected by the recipient. A more preferred test for organ compatibilityis a Human Leukocyte Antigen (HLA) matching test, but current coldischemic organ preservation approaches preclude the use of this test,which can often require 12 hours or more to complete.

Using conventional approaches, injuries caused by ischemia increase as afunction of the length of time an organ is maintained ex vivo. Forexample, a lung may typically be preserved ex vivo for only about 6 toabout 8 hours before it becomes unusable for transplantation. A hearttypically may be preserved ex vivo for only about 4 to about 6 hoursbefore it becomes unusable for transplantation. These relatively brieftime periods limit the number of recipients who can be reached from agiven donor site, thereby restricting the recipient pool for a harvestedorgan. Even within the time limits, the organs may nevertheless besignificantly damaged. A significant issue is that there may not be anyobservable indication of the damage. Because of this, less-than-optimalorgans may be transplanted, resulting in post-transplant organdysfunction or other injuries. Thus, it would be desirable to developtechniques that can extend the time during which an organ can bepreserved in a healthy state ex vivo. Such techniques would reduce therisk of post-transplant organ failure and enlarge potential donor andrecipient pools.

Prolonged and reliable ex vivo organ care would also provide benefitsoutside the context of organ transplantation. For example, a patient'sbody, as a whole, can typically tolerate much lower levels of chemo-,bio- and radiation therapy than many particular organs. An ex vivo organcare system would permit an organ to be removed from the body andtreated in isolation, reducing the risk of damage to other parts of thebody.

In view of the foregoing, improved systems, methods, and devices forcaring for an organ ex vivo are needed.

SUMMARY OF THE INVENTION

The invention addresses the deficiencies in the state of the art by, invarious embodiments, providing improved systems, methods, solutions anddevices relating to portable ex vivo organ care.

In general, in one aspect, the invention features a lung care systemthat includes: a portable multiple use module including a portablechassis, a single use disposable module including: an interface adaptedto couple the single use disposable module with the multiple use modulefor electromechanical interoperation with the multiple use module; and alung chamber assembly having a first interface for allowing a flow of aperfusion fluid into the lung, a second interface for allowingventilation of the lung with a ventilation gas, and a third interfacefor allowing a flow of the perfusion fluid away from the lung, the lungchamber assembly including a dual drain system for carrying the flow ofthe perfusion fluid away from the lung, the dual drain system comprisinga measurement drain for directing a part of the perfusion fluid flow toa sensor of a perfusion fluid gas content and a main drain for receivinga remaining part of perfusion fluid flow. In one embodiment, the lungcare system includes a drainage system for draining the perfusion fluidfrom the lung chamber assembly, the drain system including a measurementconduit and a main drain conduit, the measurement conduit furtherdirecting a flow of perfusion fluid to a sensor that is adapted tomeasure a perfusion fluid gas content.

Other embodiments include one or more of the following features. Thedual drain includes a vessel for receiving the perfusion fluid flow, andoverflow from the vessel flows to the main drain. The system includes apump for the circulating the perfusion fluid, and a ventilation systemfor ventilating the lung with a gas having a predetermined composition.The gas includes oxygen, carbon dioxide. The portable multiple usemodule includes a lung console for providing at least one of electrical,pneumatic, and mechanical control of the disposable module; the lungconsole includes a ventilation controller for controlling ventilation ofthe lung, and includes a mechanical actuator for actuating a bellows tocause flow of gas into the lung. The lung console pneumatic controlsystem controls one or valves in a ventilation gas circuit connected tothe lung in the disposable module. The pneumatic control system controlsat least one of a bellows valve for cutting off flow between the lungand the bellows, a relief valve for venting ventilation gas, and atrickle valve for introducing gas into the ventilation gas circuit. Theventilation controller selects the gas that is used to ventilate thelung from one of an oxygenation gas, a deoxygenation gas, and amaintenance gas. The oxygenation gas is air, or a gas containing between25% and 100% oxygen. The deoxygenation gas is composed of carbon dioxideand nitrogen, and the maintenance gas is composed of oxygen, carbondioxide, and nitrogen. In one embodiment, the deoxygenation gas is about6% carbon dioxide and about 94% nitrogen, and the maintenance gas isabout 12% oxygen, about 5.5% carbon dioxide, and about 82.5% nitrogen.The multiple use module includes a perfusion fluid controller that cancontrol a level of gas content, such as oxygen, in the perfusion fluid.The perfusion fluid controller controls a perfusion fluid gas component,for example by controlling the flow of gas into a gas exchanger thatexchanges gas between the flow of gas and the perfusion fluid. The gasflowing into the gas exchanger is a deoxygenation gas that removesoxygen from the perfusion fluid. The multiple use monitor includes amonitor for displaying the status of the lung case system; the statusincludes information about the oxygen content of the perfusion fluidentering the lung and exiting the lung. It also displays real timetraces of the ventilation gas pressure and the pulmonary arterialpressure.

In general, in another aspect, the invention features a lung care modulecomprising: a single use disposable module including an interfaceadapted for attachment to the multiple use module, and a lung chamberassembly having a first interface for allowing a flow of a perfusionfluid into the lung and a second interface for allowing ventilation ofthe lung with a ventilation gas; and a drain system for draining a flowof perfusion fluid from the lung chamber assembly, the drain systemincluding a measurement conduit and a main drain conduit, themeasurement conduit further directing a flow of perfusion fluid to asensor that is adapted to measure a perfusion fluid gas content.

Other embodiments include one or more of the following features. Themodule includes a system for ventilating the lungs with one of amaintenance gas, an assessment gas, and an oxygenation gas, such as air.The system can be configured to cause the lung to rebreath a volume ofgas. The ventilation system ventilates the lung with a maintenance gashaving a composition of about 12% oxygen, about 5.5% carbon dioxide, andabout 82.5% nitrogen. The lung is ventilated by using a mechanicallyactuated bellows. The ventilation system further includes a tricklevalve for introducing a flow of maintenance gas, and a relief valve forventing excess gas. The second interface to the lungs comprises atracheal cannula, which has an insertion portion for inserting into thetrachea, and a connector portion for connecting to the ventilation gascircuit. The first interface to the lungs includes a pulmonary arterycannula, which includes an insertion portion for inserting into thepulmonary artery and a connector portion for connecting to the perfusionfluid circuit. It also includes a pressure transducer connector definingan opening into a lumen of the connector portion near the insertion tubefor positioning a pressure transducer near a point of entry of theperfusion fluid into the lung. The pressure transducer connector furtherprovides a channel for the pressure transducer to be remotely vented.

In general, in yet another aspect, the invention features a lung chamberassembly comprising: a housing having a bottom including at least onehousing drain, and walls; a support surface for supporting a lung, thesupport surface defining a drain and drainage channels leading to thedrain for draining a perfusion fluid exiting the lung; an openable lidthat provides a sealable connection to the walls of the housing; a firstinterface for allowing a flow of the perfusion fluid into the lung; asecond interface for allowing ventilation of the lung; and a thirdinterface for allowing a flow of the perfusion fluid away from the lung.

Other embodiments include one or more of the following features. Thehousing includes a drain system for carrying the flow of the perfusionfluid away from the lung, the drain system comprising a measurementdrain for directing a part of the perfusion fluid flow to a sensor of aperfusion fluid gas content and a main drain for receiving a remainingpart of perfusion fluid flow. The drain system has a region forcollecting the flow of perfusion fluid away from the lung into a poolthat feeds the measurement drain, the measurement drain having adrainage capacity less than a flow rate of the perfusion fluid away fromthe lung. Flow of perfusion fluid overflowing the region flows to themain drain. In some embodiments, the drain system further includes awall partially surrounding the measurement drain, the wall partiallyblocking a flow of perfusion fluid from the measurement drain to themain drain, the wall promoting formation of a pool of perfusion fluidabove the measurement drain. The housing of the lung chamber definesopenings that provide sealed passage through the housing of a pulmonaryartery cannula, a pulmonary artery pressure transducer conduit, and atracheal cannula. In some embodiments the perfusion fluid exits the lungthrough an exposed left atrial cuff, and flows into a drainage system.In other embodiments, the flow of perfusion fluid exiting the lungpasses through a sealed connection to a left atrial cannula, which isconnected to a conduit that carries the perfusion fluid away from thelung. A part of the perfusion fluid flow passes an oxygen contentsensor, and the remainder flows to a reservoir.

In general, in a further aspect, the invention features a method ofevaluating a lung including: positioning the lung in an ex vivoperfusion circuit; circulating a perfusion fluid through the lung, thefluid entering the lung through a pulmonary artery interface and leavingthe lung through a left atrial interface; ventilating the lung byflowing a ventilation gas through a tracheal interface; deoxygenatingthe perfusion fluid until a predetermined first value of oxygen contentin the perfusion fluid is reached; reoxygenating the perfusion fluid byventilating the lung with an oxygenation gas until a predeterminedsecond value of oxygen content in the perfusion fluid is reached; anddetermining a condition of the lung based on a time taken for the lungto cause the oxygen content level in the perfusion fluid to change fromthe first value of oxygen content to the second value of oxygen content.

Other embodiments include one or more of the following features. Theperfusion fluid is deoxygenated by ventilating the lung with aventilation gas comprising carbon dioxide and nitrogen, for exampleabout 5.5% carbon dioxide and about 94.5% nitrogen. The perfusion fluidis deoxygenated by circulating the perfusion fluid through a gasexchange device, the gas exchange device being in fluid communicationwith a ventilation gas comprising carbon dioxide and nitrogen, the gasexchange device altering a composition of oxygen in the perfusion fluidby gas exchange between the ventilation gas and the perfusion fluid. Thepredetermined first value of oxygen content corresponds to a red bloodcell saturation of about 73%. The oxygenation gas is air, or a gascomprising between about 25% and about 100% oxygen. The predeterminedsecond value of oxygen content corresponds to a red blood cellsaturation of about 93%. The perfusion fluid flows at a rate of about1.5 liters per minute, and is warmed by a heater to a near-physiologictemperature level. The perfusion fluid is composed of whole blood, or ofa blood product, such as blood partially depleted of leukocytes, orpartially depleted of platelets. Various therapeutics are delivered tothe ling during perfusion via the perfusion fluid, or through thetracheal interface using a nebulizer or a bronchoscope. Oxygen levels inthe perfusion fluid are measured using a pulse oxymeter that determinesthe red blood cell saturation in the fluid.

In general in a further aspect, the invention features a method ofpreserving a lung ex vivo comprising: circulating a perfusion fluidthrough the lung, the fluid entering the lung through a pulmonary arteryinterface and leaving the lung through a left atrial interface;ventilating the lung through a tracheal interface by flowing a captivevolume of a ventilation gas back and forth between the lung and avariable volume chamber; and introducing into the captive volume anadditional volume of the ventilation gas and venting excess ventilationgas from the captive volume to maintain a predetermined composition ofthe ventilation gas and to maintain a minimum gas pressure of thecaptive volume.

Other embodiments include one or more of the following features. Theventilation gas includes a composition of oxygen, carbon dioxide and aninert gas, such as nitrogen. The perfusion fluid reaches an equilibriumlevel corresponding to a predetermined composition of the ventilationgas. The predetermined composition of the ventilation gas includes about5-20% oxygen and about 2-10% carbon dioxide. A gas content of theperfusion fluid reaches an equilibrium level, the equilibrium levelhaving a hemoglobin saturation level of about 88%-98%.

The predetermined composition of the ventilation gas includes about 12%oxygen and about 5.5% carbon dioxide. The hemoglobin saturation level ofthe perfusion fluid entering the lung reaches an equilibrium level ofabout 90-95% and a hemoglobin saturation level of the perfusion fluidleaving the lung reaches an equilibrium level of about 90-95%. Theoxygen content of the perfusion fluid entering the lung is lower thanphysiologic levels, and the oxygen content of perfusion fluid leavingthe lung is higher than physiologic levels. The following parameters areused in certain embodiments: the additional flow of ventilation gas isabout 400-600 mL per minute; the captive volume is about 400-1200 mL;the minimum gas pressure of the captive volume is about 4-8 cm of H₂O;and the maximum pressure of the ventilation gas is about 12-22 cm ofH₂O. Excess ventilation gas is vented through a relief valve incommunication with the captive volume. The variable volume chamber is abellows; compressing the bellows causes the flow of ventilation gas intothe lung. The pulmonary artery interface includes a pulmonary arterycannula, a portion of the pulmonary artery cannula being inserted into apulmonary artery of the lung. The perfusion fluid to flows away from thelung through an exposed left atrial cuff of the lung, or through asealed or semi-sealed connection between the left atrial cuff and a leftatrial cannula. The tracheal interface includes a tracheal cannula, aportion of the tracheal cannula being inserted into a trachea of thelung. The method includes measuring a first level of oxygen content inthe perfusion fluid flowing into the lung and a second level of oxygencontent in the perfusion fluid flowing out of the lung. The oxygenmeasurement involves measuring at least one of a level of oxygensaturation of hemoglobin in the perfusion fluid and a partial pressureof oxygen in the perfusion fluid flowing into the lung and flowing outof the lung. The perfusion fluid includes a blood product, and candeliver therapeutics to the lung. The gas exchange in the lung betweenthe ventilation gas and the perfusion fluid causes the level of one ormore gases, such as oxygen and carbon dioxide, in the perfusion fluid toreach equilibrium values. The lung may be preserved for a period ofabout 3-24 hours when maintained with the equilibrium levels of gas.

BRIEF DESCRIPTION OF THE DRAWINGS

The following figures depict illustrative embodiments of the inventionin which like reference numerals refer to like elements. These depictedembodiments may not be drawn to scale and are to be understood asillustrative of the invention and not as limiting.

FIGS. 1A-1B are a schematic diagram of the described embodiment of aportable organ care system. FIG. 1B shows the gas-related components ofthe lung perfusion module.

FIG. 2 is a schematic diagram of the lung perfusion circuit of thedescribed embodiment.

FIG. 3 is a schematic diagram of the gas loop of the organ care systemin maintenance mode, according to the described embodiment.

FIG. 4 is a schematic diagram of the gas loop of the organ care systemin assessment mode, according to the described embodiment.

FIGS. 5A-5B are a schematic diagram of the lung ventilator pneumaticcircuit, according to the described embodiment.

FIG. 6 is a diagram showing a typical pressure waveform in the lung overa breathing cycle, according to the described embodiment.

FIGS. 7A-7E show examples of tracheal cannulae, according to thedescribed embodiment.

FIGS. 8A-8F show examples of pulmonary artery cannulae, according to thedescribed embodiment.

FIGS. 9A-9F show lateral views of the pulmonary artery cannulaeillustrated in FIGS. 8A-8F.

FIG. 10 is an illustration of a left atrium cannula.

FIG. 11 is a screenshot of the monitor of the organ care system inmaintenance mode, according to the described embodiment.

FIG. 12 is a screenshot of the monitor of the organ care system inmaintenance mode showing the configuration menu maintenance tab,according to the described embodiment.

FIG. 13 is a screenshot of the monitor of the organ care system incontinuous assessment mode, according to the described embodiment.

FIG. 14 is a screenshot of the monitor of the organ care system insequential assessment mode, deoxygenation submode, according to thedescribed embodiment.

FIG. 15 is a screenshot of the monitor of the organ care system showingthe configuration menu for the sequential assessment submode setting,according to the described embodiment.

FIG. 16 is a screenshot of the monitor of the organ care system insequential assessment mode, hold submode, according to the describedembodiment.

FIG. 17 is a screenshot of the monitor of the organ care system insequential assessment mode, oxygenation submode, according to thedescribed embodiment.

FIG. 18 is a screenshot of the monitor of the organ care system showingthe configuration menu for the assessment tab, according to thedescribed embodiment.

FIG. 19 is a screenshot of the monitor of the organ care system showingthe configuration menu for the ventilator settings, according to thedescribed embodiment.

FIG. 20 is a screenshot of the monitor of the organ care system showingthe configuration menu for the lung tab, according to the describedembodiment.

FIG. 21 is a screenshot of the monitor of the organ care system showingthe configuration menu for the system tab, according to the describedembodiment.

FIG. 22 is an illustration of the organ care system drawn from a45-degree from the front view, according to the described embodiment.

FIG. 23 is a side view illustration of the organ care system, accordingto the described embodiment.

FIG. 24 is a front view illustration of the organ care system, accordingto the described embodiment.

FIG. 25 is an illustration of the organ care system with the side panelsremoved, according to the described embodiment.

FIG. 26 is an illustration of the organ care system with the lungperfusion module removed, according to the described embodiment.

FIG. 27 is an illustration of the lung perfusion module, according tothe described embodiment.

FIG. 28 is an exploded illustration of the lung chamber, according tothe described embodiment.

FIG. 29 is an illustration of the lung support surface, housing, andfront piece of the lung chamber, according to the described embodiment.

FIG. 30 is an illustration of the lung support surface, housing, andfront piece of the lung chamber, showing the tracheal cannula and the PAcannula, according to the described embodiment.

FIG. 31 is a flow diagram showing steps performed at the lung donor siteprior to place the lungs into the organ care system, according to thedescribed embodiment.

FIG. 32 is a flow diagram showing steps performed during transport ofthe lungs from the donor site to the recipient site, according to thedescribed embodiment.

FIG. 33 is a flow diagram showing steps performed at the lung recipientsite to remove the lungs from the organ care system and transplant theminto the recipient, according to the described embodiment.

FIG. 34 is a flow diagram showing steps performed during continuousassessment of lungs ex vivo.

FIG. 35 is a flow diagram showing steps performed during sequentialassessment of lungs ex vivo.

DETAILED DESCRIPTION

As described above in summary, the described embodiment generallyprovides improved approaches to ex vivo lung care, particularly in an exvivo portable environment. The organ care system maintains a lung in anequilibrium state by circulating a perfusion fluid through the lung'svascular system, while causing the lung to rebreath a speciallyformulated gas having about half the oxygen of air. The perfusion fluidcirculates by entering the pulmonary artery (PA) via a cannula insertedinto the PA. After passing through the lung, the perfusion fluid exitsthe lung from an open, uncannulated left atrium (LA) where it drainsinto a reservoir. A pump draws the fluid out of the reservoir, passes itthrough a heater and a gas exchanger, and back into the cannulated PA.In the described embodiment, the perfusion fluid is derived from donorblood. In alternative embodiments, the perfusion fluid is blood-productbased, synthetic blood substitute based, a mixture of blood product andblood substitute, or derived from blood from a blood bank.

The described embodiments enable a lung to be maintained ex vivo forextended periods of time, such as, for example, 3-24 or more hours. Suchextended ex vivo maintenance times expand the pool of potentialrecipients for donor lungs, making geographic distance between donorsand recipients less important. Extended ex vivo maintenance times alsoprovide the time needed for better genetic and HLA matching betweendonor organs and organ recipients, increasing the likelihood of afavorable outcome. The ability to maintain the organ in a nearphysiologic functioning condition also enables a clinician to evaluatethe organ's function ex vivo, and identify organs that are damaged. Thisis especially valuable in the case of the lung, since lungs are oftencompromised as a direct or indirect result of the cause of the death ofthe donor. Thus even a newly harvested lung may be damaged. The abilityto make a prompt assessment of a harvested organ enables a surgeon todetermine the quality of a lung and, if there is damage, to make adetermination of the nature of the problem. The surgeon then makes adecision as to whether to discard the lung, or to apply therapy to thelung. Therapies can include recruitment processes, removing or staplingoff damaged areas of lung, suctioning secretions, cauterizing bleedingblood vessels, and giving radiation treatment. The ability to assessand, if necessary provide therapy to lungs at several stages fromharvesting to implantation greatly improves the overall likelihood oflung transplant success. In some instances, the improved assessmentcapability and extended maintenance time enables medical operators toperform physical repairs on donor organs with minor defects. Increasedex vivo organ maintenance times can also enable an organ to be removedfrom a patient, treated in isolation ex vivo, and then put back into thebody of a patient. Such treatment may include, without limitation,pharmaceutical treatments, gas therapies, surgical treatments, chemo-,bio-, gene and/or radiation therapies.

The lung care system is described below in the following order. First,an overview of the components of an illustrative organ care system isgiven. Second, illustrative operation of the system is discussed,starting with preparing a lung and mounting it in the system. Third theuse of the system for maintaining a lung is described. Two methods ofassessing a lung are then described in the fourth and fifthsections—continuous assessment mode, and sequential assessment mode.Sixth, the functioning of the lung ventilator pneumatic circuit isdescribed. Seventh, exemplary organ care system user interfaces andsystem displays are shown during lung maintenance and assessment.Eighth, illustrative implementations of the organ care system andselected components are described. In the ninth section, illustrativemodels for using the organ care system are described.

Overview of Organ Care System

FIG. 1 is a block diagram that shows the main components of an organcare system (OCS) 1000 adapted to the preservation and treatment of alung. The organ care system includes a permanent, multiple use,non-disposable section, OCS lung console 101, and a single usedisposable section, lung perfusion module 400, which is in directcontact with the physical lungs, and the gases and fluids that passthrough it. Multiple use OCS lung console 101 includes four components:OCS console 100, lung console module 200, OCS monitor 300, and probesfor measuring flow (114), and perfusion fluid oxygen and hematocritlevels (116, 118). In the described embodiment, OCS 1000 is a selfcontained, mobile and portable unit, and can readily be handled by oneperson for transport on a flat surface using wheels, or lifted by twopeople, such as when being loaded into a vehicle. When loaded with anorgan and perfusion fluid, OCS 1000 weighs about 75-100 pounds, andpreferably about 80 pounds.

OCS console 100 provides processing, temperature, and power controlservices to the system. During the manufacturing process, OCS console100 is adapted for use with OCS lung console module 200. Alternatively,OCS console 100 can be adapted for use with modules that are adapted topreserve organs other than the lung, such as the heart, liver, orkidney. OCS console 100 includes main processor 102, which is aFreescale MX1 in the described embodiment, to provide system control andprocess data. Main processor 102 distributes software to otherprocessors in the system, including lung console module controller 202,heater controller 104, OCS monitor processor 302, and pump controller(not shown). It also manages data, such as that received from flowsensor 114, pressure sensor 115, and oxygen sensors 116, 118.

Heater controller 104, which is a PIC microcontroller in the describedembodiment, controls the heating of the perfusion fluid. Pressuretransducer 223 measures the pressure of internal maintenance gas in tank221, so that the amount of gas remaining can be determined. Regulator222 converts the gas tank pressure to 25 mm Hg for use in the system.Internal maintenance gas tank 221 contains a mixture that is designed toprovide enough oxygen to maintain the lung tissue during maintenancemode, described below. In the described embodiment, the maintenance gasis composed of 12% oxygen, 5.5% carbon dioxide, and 82.5% nitrogen. Insome embodiments, OCS console 100 also includes an internaldeoxygenation gas tank, regulator, and pressure transducer (not shown),which is used during assessment of the lungs. Assessment modes aredescribed in a later section.

The functions specific to the preservation of a lung (as opposed toother organs) are controlled by lung console module 200. Lung consolemodule 200 is connected to OCS console 100 with data, power, and gasconnections. The data connection links main processor 102 on OCS console100 with lung console module controller 202, which is implemented on aPIC microcontroller in the described embodiment. The power connectionlinks the OCS console's power control module 106 with power converter218, which in turn supplies power at the appropriate voltage to thepowered components within lung console module 200. The gas connectionruns from maintenance gas regulator 222 to gas selector switch 216,which selects whether maintenance gas or deoxygenation gas flows intothe lungs. In the described embodiment, deoxygenation gas tank 501 isexternal to OCS 100 and maintenance gas tank 221 is located internal toOCS console 100. In an alternative embodiment, OCS console 100 alsoincludes an internal deoxygenation gas tank. In another alternativeembodiment, an additional external maintenance gas tank 221 supplementsthe maintenance gas tank internal to the OCS console. External gas tankscan be supplied at the donor site, recipient site, or can be stowed in avehicle transporting the lungs. Since external tanks do not need to beaccommodated within the confined volume of the OCS lung console 101,they can be larger, and can supplement the limited gas supply of thesmaller internal gas tanks of OCS 1000.

Controller 202 manages the release of maintenance and assessment gasesby controlling the valves, gas selector switch 216, and ventilator 214,thus implementing the preservation of the lungs in maintenance mode, orthe assessment of the lungs in one of the assessment modes. Blood gassolenoid valve 204 controls the amount of gas flowing into blood gasexchanger 402. Airway pressure sensor 206 samples pressure in the airwayof lungs 404, as sensed through isolation membrane 408. Relief valveactuator 207 is pneumatically controlled, and controls relief valve 412.The pneumatic control is carried out by inflating or deflating orificerestrictors that block or unblock the air pathway being controlled. Thismethod of control allows complete isolation between the control systemsin lung console module 200 and the ventilation gas loop in lungperfusion module 400. Pneumatic control 208 controls relief valve 207and bellows valve actuator 210. The pneumatic control circuits of lungconsole module 200 are described in detail below. Trickle valve 212controls delivery of gas to the airway of lungs 404. Ventilator 214 is amechanical device with an actuator arm that causes bellows 418 tocontract and expand, which causes inhalation and exhalation of gas intoand out of lungs 404.

OCS monitor 300 provides user control of OCS 1000 via buttons, anddisplays data from the system's sensors that indicate the state of thelungs and of the various subsystems within OCS 1000. Monitor 300 isuniversal, i.e., it can be used for any organ. It includes monitorprocessor 302 that runs the software controlling monitor 300 anddisplays data on LCD 304. In the described embodiment, monitor processor302 is a Freescale MX1. Examples of various screen displays aredescribed below in connection with the usage modes of OCS 1000. OCSmonitor 300 includes four control buttons for the user: menu button 306brings up the configuration menu; alarm button 308 silences the speaker;pump button 310 controls the circulatory pump; and action button 312provides access to certain organ-specific actions, such as ventilatorcontrol, or to system actions, such as saving a session file to anexternal memory card. Other controls can also be included, such as aknob for controlling a value or selecting an item.

OCS lung console 101 includes probes that measure properties ofcirculating perfusion medium 250, also referred to herein as perfusionfluid and perfusate. Flow probe 114 measures the rate of flow ofperfusion fluid 250 through the system. In the described embodiment,flow probe 114 is placed on the perfusate line as it leads towards thepulmonary artery. Pressure sensor 115 measures pulmonary arterialpressure at the point of entry of perfusion fluid 250 into the lungs.Two oxygen saturation sensors 116 and 118 sense the amount of oxygen inperfusion fluid 250 in the arterial, i.e., oxygenated, side of thecircuit and in the venous, i.e., de-oxygenated, side of the circuit.

Lung perfusion module 400 is in direct contact with the gas and fluidcircuits flowing through lungs 404. It is therefore necessary to isolateit from the rest of OCS 1000 so that no tissue or fluids that come intocontact with the organ ever come into contact with OCS lung console 101.This is achieved by connecting it to the OCS lung console 101 only viaone-way gas lines, or via isolated control gas for pneumatic control, orby means of a mechanical actuator (for the bellows). The entire lungperfusion module 400, which contains all of the tissue andblood-contacting surfaces for the whole system, is disposable and isreplaced for each new lung that is placed in OCS 1000. All tissue andblood-contacting surfaces are part of disposable lung perfusion module400, which is manufactured from injection-molded components usinginexpensive biocompatible materials that can easily be sterilized. Lungperfusion module 400 is shaped and sized for coupling with OCS console100. The coupling between lung perfusion module and the OCS console caninvolve an interlocking mechanism, or other mechanism that secures theperfusion module to the OCS console or otherwise maintains the perfusionmodule in a desired position relative to the OCS console. In thedescribed embodiment, lung perfusion module is easily attached to anddetached from OCS console 100 with a mechanical hinge and claspmechanism, described below in connection with FIG. 22. It is alsoconnected by plug-in electrical and optical connections.

Lung perfusion module 400 includes bellows 418, which is actuated byventilator 214. Ventilator 214 uses a mechanical actuator arm tocompress and release bellows 418. Compressing the bellows causes gas tobe inspired by lungs 404; releasing the bellows causes it to expand andallow gas to be expired by the lungs. The distance traveled by themechanical actuator in compressing bellows 418 determines the tidalvolume, i.e., the volume of gas inhaled by lungs 404. Gas flowing in andout of the lungs passes through gas filter 410, which prevents anyfluids produced by the lungs from entering the gas loop.

In order to ensure isolation of the gas in the lung perfusion module 400ventilation loop, all lung gas connections between lung perfusion module400 and OCS lung console 101 include membranes that prevent gas fromflowing back into OCS lung module 101. Isolation membranes are notneeded for pneumatic control gas connections, such as from relief valveactuator 207 and bellows valve actuator, because this gas has no contactwith the organ. One-way gas flow valves that only permit flow into thelung perfusion module are automatically isolated from gas in theventilation loop; such valves include trickle valve 212 and blood gassolenoid valve 204. Airway pressure sensor 206 samples the gas linepressure via isolation membrane 408 that prevents any exchange of gasbackwards towards OCS lung console 101.

Perfusion module 400 includes blood gas exchanger 402, which includes aperfusate/gas exchange membrane that enables the infusion of a gas intothe perfusate stream. The perfusate circulates through circuits 406 and407 between lungs 404 and gas exchanger 402. The organ chamber supportslungs 404 and channels the perfusate coming out of the lungs from theleft atrium in a manner that facilitates accurate measurement ofarterial oxygen content levels. A detailed description of the perfusioncircuit and the organ chamber is provided below.

Perfusion module 400 also includes relief valve 412, which provides forcontrolled release of gas to be expired to the outside, serving toreduce gas pressure within the ventilator gas loop. Bellows valve 414controls the gas flow to or from the lungs. Check valve 416 is a one-wayvalve which allows external air to be drawn into the ventilation system.Bellows 418 expands and contracts; when the ventilator system is used inrebreathing mode, the bellows exchanges a substantially fixed volume ofgas with the lungs as it expands and contracts.

FIG. 2 illustrates the lung perfusion circuit. The circuit is housedentirely within the lung perfusion module, and all its components aredisposable. Perfusion fluid 250 circulates within the perfusion circuit,passing through various components of lung perfusion module beforepassing through the vascular system of lungs 404. Pump 226 causesperfusion fluid 250 to flow around the lung perfusion circuit. Itreceives perfusion fluid 250 from reservoir 224, and pumps the solutionthrough compliance chamber 228 to heater 230. Compliance chamber 228 isa flexible portion of tubing that serves to mitigate the pulsatilenature of pump 226. Heater 230 replaces heat lost by perfusion fluid 250to the environment during circulation of the fluid. In the describedembodiment, the heater maintains perfusion fluid 250 at or near thephysiologic temperature of 30-37 degrees C., and preferably at about 34degrees C. After passing through heater 230, perfusion fluid 250 flowsinto gas exchanger 402. Like the lung, gas exchanger 402 enables gasesto be exchanged between gas and perfusion fluid 250 via a gas-permeable,hollow fiber membrane. However, the gas exchanger has an effective gasexchange surface area of about 1 square meter, which is only a fractionof the 50-100 square meter effective exchange area of the lungs. Thusgas exchanger 402 has only a limited gas exchange capability compared tothe lungs. Blood gas solenoid valve 204 regulates the supply of gas intogas exchanger 402. The composition of gas supplied to gas exchanger isdetermined by which mode the OCS is in, described in detail below. Forexample, when OCS 1000 is in sequential assessment mode, deoxygenationgas 500 is supplied to the gas exchanger during the deoxygenation phaseof the sequential assessment cycle. After passing through gas exchanger402, perfusion fluid 250 passes through flow rate probe 114, pressureprobe 115, and a perfusate oxygen probe 116. We refer to the readingsfrom oxygen probe 116 as SvO₂ since it measures oxygen in perfusionfluid 250 just before it enters the lungs, which is analogous to venousblood oxygen. Sampling/injection port 236 facilitates the removal of asample or the injection of a chemical just before perfusion fluid 250reaches the lungs. Perfusion solution then enters lungs 404 throughcannulated pulmonary artery 232.

The pulmonary artery (PA) cannula connects the perfusion circuit withthe vascular system of lungs 404. Several exemplary embodiments of apulmonary artery (PA) cannula are shown in FIGS. 8A-8F. Referring toFIG. 8A, single PA cannula 802 has single insertion tube 804 forinsertion into a single PA, and is used to cannulate the PA at a pointbefore it branches to the two lungs. To connect the cannula to thepulmonary artery, insertion tube 804 is inserted into the PA, and the PAis secured onto the tube with sutures. Insertion tube 804 of cannula 802connects to connector portion 805, which serves to position insertiontube 804 at an angle and location suitable for strain-free connection tothe pulmonary artery of lungs 404. Connection portion 805 connects tomain tube portion 808, which is attached to the perfusion fluid circuit.FIG. 9A is a lateral view of PA cannulae 802 showing the angle betweeninsertion tube 804 and connecting portion 805; in the describedembodiment, the angle is between about 15 degrees and 30 degrees, andpreferably about 22.5 degrees.

Referring to FIGS. 8B-8F, double PA cannulae 810, 820, 830, 840, and 850each have two insertion tubes 812, 814, 822, 824, 832, 834, 842, 844,and 852, 854, each pair of tubes being angled apart from the main axisof the cannula by 30, 45, 60, 75, and 90 degrees in cannulae 810, 820,830, 840, and 850 respectively. Each tube has a diameter of about 0.5 to0.72 inches at the rib, and about 0.4 to 0.62 inches on the body of theinsertion tube. The varying angles provide the surgeon with a choice ofcannulae to best accommodate the anatomy of the donor lungs. Referringto FIG. 8B, pair of insertion tubes 812 and 814 are joined to connectingportion 815 in a Y-shaped configuration. As shown most clearly in FIG.9B, connecting portion 815 is angled with respect to main tube 818; theangle is chosen to facilitate the insertion of insertion tubes 812 and814 into the pulmonary arteries of lungs 404. In the describedembodiment the angle is between 15 and 30 degrees, and preferably about22.5 degrees. Referring to FIGS. 9C-9F, a similar angle of between 15and 30 degrees, and preferably about 22.5 degrees, is shown betweenconnecting portions 825, 835, 845, 855 and their corresponding maintubes 828, 838, 848, and 858. An alternative to having PA cannulae withbranching ends angled apart at various preset angles, is to havemalleable PA cannulae that can be bent to accommodate the angle of adonor's lung vessels.

The material of manufacture of the PA cannulae is now described. In anillustrative embodiment of single PA cannula 802, insertion portion 804has a polycarbonate tip, with connector portion 805 and main tubeportion 808 being made of urethane tubing. In an alternative embodiment,insertion tube 804, connector portion 805, and main tube portion 808 areall made of a single piece of silicone of between 50 Shore A to 90 ShoreA hardness silicone, preferably of a 80 Shore A hardness silicone.Similarly, for dual PA cannulae, main tubes 818, 828, 838, 848, 858 andconnector portions 815, 825, 835, 845, 855 of double PA cannulae 810,820, 830, 840, and 850 respectively may be made of urethane, and theinsertion tubes 812, 814, 822, 824, 832, 834, 842, 844, 852, and 854 maybe made of polycarbonate. In an alternative embodiment, the entire dualtube PA cannula, i.e., the dual insertion tubes, connector portion, andmain tube, are all made of a single piece of 80 Shore A silicone. Anadvantage of silicone construction is that it is soft enough to providea good purchase and grip for lung vessels tied on to the cannulaconnector with sutures. In addition, silicone can readily be cut to therequired length at the time of attachment to the lung PA. Furthermore,silicone allows fabrication of the entire cannula in a single piecebecause it can be molded into a complex shape. Integral construction ofthe cannula eliminates transitions between separate cannula parts, whichcan produce unwanted turbulence in perfusion fluid 250, introduceimpurities, or cause leaks at the joints between separate parts. Inaddition, integral construction requires the molding of a single pieceonly, which reduces cost and increases the reliability of the cannula.

The connecting portion of each PA cannula also includes a connector forconnecting perfusate pressure transducer 115. Referring again to FIGS.8A-8F and 9A-9F, PA cannulae 802, 810, 820, 830, 840, and 850 includepressure transducer connectors 806, 816, 826, 836, 846, and 856respectively. The connector serves to allow placement of the perfusatepressure sensor at the correct location, right at the point of entry tothe lungs where the perfusate flow slows, and pressure readings are notdistorted by Bernoulli flow pressure. The pressure transducer connectorsalso provides a channel for pressure sensor 115 to be remotely vented,helping to ensure the accuracy of the pressure reading.

After passing through the lungs, the perfusate exits the lungs from theleft atrium, a portion of which is removed along with the lung duringexplantation of the lungs from the donor. Since the left atrial tissueserves as an attachment zone during transplantation of the lungs intothe recipient, it is important to leave it as undisturbed and healthy aspossible. Therefore, in the described embodiment, the left atrial cuffis not cannulated, allowing the circulating perfusate to drain from theopen left atrium and the left atrial cuff.

In an alternate embodiment, the left atrial cuff is cannulated withcage-like cannula 1002, illustrated in FIG. 10. In this embodiment, allthe LA vessels are placed inside the cannula; the excess LA tissue isthen wrapped around the cannula. The cage-like structure 1004 of LAcannula 1002 is designed to hold the left atrium open without occludingany pulmonary veins, thus helping to reduce the risk of compromising thehealth of the tissue. Inside the cannula, the perfusate flowing from thepulmonary veins is collected into tube 1006, and fed to the perfusatereservoir. Connector 1008 provides a connection point for a pressuretransducer, which can be placed inside cannula 1002 and measureperfusate pressure.

The perfusate exiting the lungs is collected in a dual drain system,using an “over flowing cup” technique to allow the sampling of newlydrained fluid before it becomes mixed with other perfusate in thereservoir. All the flow from the lungs is directed to a small cup whichfeeds a measurement drain. The capacity of this drain is restricted bythe use of small diameter tubing. Perfusate from the lungs exits at aflow rate that exceeds the capacity of the measurement drain. Excessblood overflows this small cup and is directed to the main drain andthus to the reservoir pool. The measurement drain directs a bubble freestream of newly drained perfusate toward the second oxygen probe 118 toobtain an accurate reading of arterial oxygen level, referred to asSaO2. After passing through second sampling/injection port 234, theperfusion solution completes its cycle and returns to reservoir 224. Thedual drain system is necessary only in the configuration in which theleft atrial cuff is uncannulated. But if the left atrial cuff iscannulated, such as with a cage cannula as described below, there is noneed for the dual drain system since a solid column of newly drained,bubble-free perfusate exits the cannulated left atrial cuff.

In the described embodiment, perfusion fluid 250 is composed of donorblood with the addition of heparin, insulin, vitamins, and antibiotics.Dextran serves to adjust oncotic pressure, Hematocrit levels, and pH.

The following sections describe how OCS 1000 is used to preserve andassess a lung. The preinstrumentation section describes the initialsteps in preparing OCS 1000 and the lung prior to connecting the lung tothe OCS. The maintenance mode section describes how the OCS is used topreserve the lung. The assessment mode sections describe two ways ofassessing the condition of the lungs—continuous mode and sequentialmode.

Preinstrumentation

After removing the lung from the donor, the tracheal cannula is insertedinto the trachea to provide a means of connection between the lungperfusion module 400 gas circuit and the lungs. FIGS. 7A-7E illustrate aset of exemplary tracheal cannulae. With reference to FIG. 7A, cannula700 includes tracheal insertion portion 704 to which the trachea issecured with a cable tie, or by other means. In the describedembodiment, insertion portion 704 is about 0.8 inches long. The base ofcannula 700 is preferably composed of polycarbonate, or another hardinjection-moldable, biocompatible plastic, such as acrylic, polyester,K-resin, nylon, polyethylene, or polypropylene. The over-layer overinsertion portion 704 is preferably composed of a soft silicone rubber;alternative materials for the over-layer are other soft, biocompatibleextruded or moldable materials such as polyurethane, thermoplasticelastomers, and other rubber materials. Adjacent to tracheal attachmentportion 704 is flexible section 706, which is preferably composed ofpolyurethane, or one of the other biocompatible materials listed aboveas being suitable for the insertion portion over-layer. Insertionportion 704 and its over-layer, and flexible portion 706 are injectionmoldable, with the silicone over-layer being overmolded onto the basepart. In an alternative embodiment, the silicone over-layer isseparately molded, or extruded and stretched over the base.

At the end of insertion portion 704 that is inserted into the trachea isrib 703; the rib helps secure insertion portion 704 at the insertedlocation within the trachea, and is secured with a cable tie placedaround the trachea. At the opposite end of insertion portion 704, secondrib 705, having a diameter about 0.2 inches greater than the base partdiameter of insertion portion 704, acts as a stop for the siliconeover-layer and as a stop for the trachea. Past rib 705 is a tubing barbfitting that is about 0.5 inches long, and has an angled barb to hold a0.5 inch diameter tube. On the base piece that goes to lung OCS lungchamber connector 710, there is a second tubing barb fitting that isabout 0.5 inches long, having an angled barb to hold a 0.5 inch diametertube.

Flexible portion 706 can be clamped to seal off air flow in and out oflungs 404. For example, clamping of section 706 is used to maintain astatic inflation of lungs 404 after explantation and before connectionsto the gas circuit of the OCS. Static inflation serves to preventcollapse of the lungs, and the consequent damage to the alveoli. Instatic inflation, the lungs are inflated to a pressure of about 20centimeters of water. The tracheal cannula is then clamped off atflexible section 706.

Near the end of flexible section 706 furthest from the trachealinsertion portion, cannula 700 includes locknut 708 for securing thecannula to the lung chamber. Locknut 708 is mounted on a stepped portionof the cannula tube. Adjacent to locknut 708, 0.7 inch-long 15 mm.connector 710, serves to connect the cannula to a standard ventilatorconnector, which connects the lung to the gas circuit of the OCS.Tracheal cannulae are designed to accommodate donor lungs having varyingtracheal diameters according to the size of the donor. FIG. 7Aillustrates tracheal cannula 700 having insertion portion tip diameter702 of 0.9 inches. In FIGS. 7B, 7C, 7D, and 7E, cannulae havinginsertion portion tip diameters 722, 742, 762, 782 of 0.85, 0.80, 0.75,and 0.70 inches of insertion portions 724, 744, 764, and 784respectively are shown. Cannulae having insertion portion diameterssmaller than 0.7 inches, or larger than 0.9 inches may be needed toaccommodate lungs from certain donors.

Before receiving the lungs, the OCS perfusion circuit is primed withdonor blood, priming solution, and drugs. This perfusate is thencirculated and warmed. During this phase, gas exchanger 402 establishesblood gases that correspond to maintenance mode. This is achieved bysetting gas selector switch 216 to allow maintenance gas to flow intothe gas exchanger, and by duty cycle modulating gas exchanger valve 204to provide a low average flow of maintenance gas through the gasexchanger. The exchange of gases in the gas exchanger causes thecirculating perfusate to reach equilibrium with the maintenance gas,establishing the desired maintenance perfusate gas levels of O₂ and CO₂.The perfusate pH is controlled by the CO₂ level. These preparatory stepsensure that when the lung is instrumented on the OCS, the perfusate hasalready reached the maintenance gas levels, which helps accelerate thelungs' transition to maintenance mode.

Maintenance Mode

Maintenance mode places the lungs in a safe, stable condition so as toallow them to be preserved for an extended period of time. By placingthe lungs in equilibrium with a gas containing oxygen to meet the lung'smetabolic demands and carbon dioxide to control blood pH, themaintenance gas satisfies the lung's cellular requirements. Oxygenconsumption in the lung is so low that each breath can be substantiallyrecycled, dramatically reducing the volume of fresh gas consumption.Since it is normally necessary to transport donated organs to adifferent site where the recipient is located, reducing the amount ofgas needed to support the lungs, and thereby increasing the portabilityof the system, is a significant benefit.

When the lungs are placed within the organ chamber, the tracheal cannulais connected to the system gas line, which is placed in pause mode. Inpause mode, bellows 418 are in a fully expanded state, i.e., prepared toperform the first lung inhalation. The clamp on the tracheal cannula isremoved, and the pressures in the lung and in the gas line equalize.Inhalation then commences.

FIG. 3 is an illustration of the functioning of the OCS in maintenancemode. In maintenance mode the ventilator system moves a captive volumeof gas back and forth between the lungs and the bellows, causing thelungs to rebreath the gas. In addition, a small amount of maintenancegas 220 is trickled into the ventilation circuit during each breaththrough valve 212. Excess gas is exhausted from the circuit throughrelief valve 412 in order to prevent pressure buildup and maintain thedesired minimum gas pressure in the system. In the described embodiment,maintenance gas 220 is composed of about 9-15% oxygen, and preferablyabout 12% oxygen, about 4-7% carbon dioxide, and preferably about 5.5%carbon dioxide, with the balance being nitrogen.

The composition of maintenance gas 220 includes an amount of oxygen thatis about one half that of air, and an amount of carbon dioxide thatmaintains a near-physiologic pH level in perfusion fluid 250. Inmaintenance mode, an equilibrium is achieved between maintenance gas 220and perfusate gas levels. In this equilibrium, there is only a smalldifference between the oxygen level in perfusion fluid 250 enteringlungs 404, i.e., the venous level PvO₂, and the level exiting lungs 404,i.e., the arterial level PaO₂. The composition of maintenance gas 220 ischosen to achieve perfusate oxygen levels that depart as little aspossible from physiologic blood gas levels. Too high an oxygen contentresults in a venous oxygen level that is well above physiologic levels;conversely, too low an oxygen level results in an arterial oxygen levelthat is well below physiological levels. The preferred maintenance gascomposition is a compromise between these levels, achieving equilibriumarterial and venous oxygen levels in perfusion fluid 250 that areapproximately mid-way between physiologic venous and arterial levels.The preferred oxygen component of about 12% also provides more thansufficient oxygen to serve the lungs' metabolic needs. Furthermore, a12% oxygen level is close to the oxygen level in the alveoli of ahealthy lung breathing air, because there is a gradient between theoxygen level in the trachea and the level in the alveoli caused by gasexchange along the airway path into the lungs. This gradient is absentin the case of lungs 404 in maintenance mode, when maintenance gas isbeing rebreathed, and the oxygen level is about 12% throughout the lung.

Initially, when the lungs are first connected to the OCS gas line, thegas loop is filled with air, not with maintenance gas. Thus, ventilationof the lungs is initially with air. As the maintenance gas is trickledin, and excess gas is released, the composition of gas in the gas loopsoon changes to that of the maintenance gas.

In maintenance mode, gas selector valve 216 (FIG. 1) is set to selectmaintenance gas tank 221. Gas exchanger valve 204 is always closed inmaintenance mode because gas exchanger 402 is not used. Bellows valve414 is always open to maintain the exchange of gas between the bellowsand the lungs. Referring to FIG. 3, passive check valve 416 allows airinto the circuit under suction conditions, but remains closed duringmaintenance mode because the ventilation circuit always has positivepressure.

At the start of each maintenance mode cycle, bellows 418 are at thefully open position and the lungs are at their minimum volume. Duringthe cycle, bellows 418 compresses, driving gas into the lungs. The lungsexpand to accommodate this gas volume, causing a rise in pressure. Whenthe specified volume of gas has been delivered, bellows 418 pauses for aspecified plateau time before starting the exhalation portion of thecycle. During exhalation, bellows 418 returns to its original fullyexpanded state, and the lungs relax. The next ventilation cycle beginsafter an interval set by the specified respiration rate. The extent towhich bellows 418 compress during the inhalation phase of each cycle isdetermined by the user-specified tidal volume, typically between 400 and1200 mL.

FIG. 6 shows typical respiration pressure waveform 650 for eachventilation cycle. At the start of the cycle, the pressure is set topositive end expiratory pressure (PEEP) value 652, which isapproximately 5 cm of H₂O. As the bellows compress in inhalation portion654 of the cycle, the pressure increases to peak pressure 656, andremains at the peak pressure for plateau portion 658 of the cycle. Inthe described embodiment, the peak pressure is about 20 cm H₂O. Inexhalation portion 660 of the cycle, the pressure decreases until itreaches the desired PEEP level at the end of the cycle. Duration 662 ofa complete ventilation cycle is set by the user-selected respirationrate, and is typically about 6 seconds.

Two other events occur in each maintenance mode ventilation cycle.During inhalation phase 654, trickle valve 212 opens briefly allowing aspecific volume of calibrated maintenance gas into the circuit. Later,at the end of exhalation phase 660, relief valve 412 opens briefly toexhaust excess gas to the outside air until the desired PEEP is reached.The opening of trickle valve 212 and relief valve 412 are illustrated inFIG. 6 by traces 664 and 666 respectively.

The average flow of maintenance gas into the ventilation loop isspecified by the user, and is typically 500 ml/min. At a ventilationrate of 10 breaths per minute, trickle valve 212 allows 50 ml ofmaintenance gas into the circuit on each cycle. When ventilating with atypical tidal volume of 600 ml, the injection of maintenance gas on eachcycle amounts to only about 10% of the tidal volume, and thus has only asmall effect on any given ventilation cycle. The flow rate ofmaintenance gas is usually set at the minimum level required to keep thegas composition in the gas loop close to the maintenance gas levelsdespite the tendency of the lungs' metabolism to decrease the oxygenlevel and increase the CO₂ level. Injection of maintenance gas is alsoused to maintain the desired PEEP level in the system. The amount of gasleakage from the lungs and from respiration fittings also affects theamount of maintenance gas injected.

Since the metabolic activity of the lung is low, it requires littleoxygen for support, and produces only a small amount of carbon dioxide.Thus the lung's own metabolism has only a small effect on thecomposition of the ventilation gas and perfusate gases. Sincemaintenance gas is injected into the gas line during each ventilationcycle, the composition of ventilation gas and of the perfusate gasesrapidly reach the same composition, namely that of the maintenance gas.Once this situation occurs, the lungs are in a state of equilibrium withthe maintenance gas. In the equilibrium state, the perfusate oxygenlevels achieve steady state values. The SaO₂ steady state level is inthe range of about 93-95%, a little lower than the physiologic levels.The corresponding steady state SvO₂ level is in the range of about90-91%, which is higher than physiologic levels. Thus in maintenancemode, the difference between saturation levels in perfusion fluid 250across the lungs is lower than the physiologic difference. The higherSvO₂ results, in part, from the absence of the deoxygenating effect ofthe body tissue, which is present in the physiologic case. The lowerSaO₂ level is caused in part by ventilation of the lungs withmaintenance gas, which has only about half the oxygen content of air.

In a refinement of maintenance mode ventilation, the system shortens thebellows compression stroke to account for the volume of gas contributedby trickle valve 212, so as to maintain an accurate and constant tidalvolume delivery to the lungs.

Assessment Mode—Continuous

FIG. 4 is a schematic diagram showing the various components involved inperforming lung assessments. In continuous mode assessment, the systemmimics body processes by inhaling air into the lungs, and then removingthe perfusate oxygen before the perfusion fluid returns to the lungs. Inthe body the removal of the oxygen is accomplished by tissues; in theOCS it is accomplished by deoxygenation gas flowing through the gasexchanger. Continuous mode assessment tests the gas exchange capabilityof the lungs by measuring how well the lungs can reoxygenate the blood.This measurement is performed by measuring venous and arterial bloodoxygen levels. The scoring of lung performance in continuous assessmentmode is discussed further below.

FIG. 34 is a flow diagram showing the principal steps involved inperforming continuous assessment of the lungs. In step 3402,deoxygenation gas is flowed through gas exchanger 402. This isaccomplished using gas selector switch 216, which is set to selectdeoxygenation gas 500, and by opening gas exchanger valve 204 to connectgas exchanger 402 to the deoxygenation gas supply. In the describedembodiment, deoxygenation gas is composed of 4-7% CO₂ and preferably 6%CO₂, with the balance being nitrogen. Trickle valve 212 is kept closedin this mode. In step 3404, the lungs are ventilated with air or anotherventilation gas using bellows 418, which deliver a fresh breath of airor other ventilation gas to the lungs during the inhalation phase ofeach cycle.

FIG. 6 shows the gas pressure profile and valve settings in a continuousmode ventilation cycle. When a cycle begins, bellows 418 are at thefully open position, the lungs are at their minimum volume, and thepressure is at PEEP level 652. Bellows valve 414 is opened 668 and thebellows compress, driving gas into the lungs in inhalation phase 654.The lungs expand to accommodate the gas, and there is an accompanyingrise in pressure. When bellows 418 has delivered the specified volume ofgas, the system pauses for a user-specified plateau time 658 (alsoreferred to as dwell time), before starting exhalation phase 660 of thecycle. During the exhalation the connection between the bellows and thelungs is sealed off by closing bellows valve 414, 670. On the lung sideof the circuit, relief valve 412 is opened 672 to exhaust gas from thelungs until the PEEP level is reached, at which point relief valve 412closes 674. In the meantime, bellows 418 is expanded to the fullyextended position. This creates suction on the bellows side, which isrelieved by passive check valve 416 that lets in external air to fillthe bellows in preparation for the next inhalation cycle. The nextventilation cycle begins at a time determined by the user-specifiedrespiration rate. Thus, the coordinated actuation of bellows valve 414and relief valve 412 during each cycle causes continuous ventilation ofthe lungs with fresh air.

In an alternative embodiment, bellows valve 414 is closed at the end ofinhalation phase 654, before plateau 658. This allows bellows expansionto begin immediately after the inhalation phase.

A gas other than air can be supplied to the inlet of check valve 416.Indeed, gas of any desired composition can be provided. For example, thegas can be provided from common gas entrainment devices that provideoxygen enrichment in a hospital. Such devices can supply ventilation gasat standard 50% or 100% oxygen levels.

While deoxygenation gas is flowing through gas exchanger 402 and thelung is being ventilated with air, perfusate is circulated through thelung and gas exchanger, as shown in FIG. 34, step 3406. In order toapproximate to physiologic conditions while assessing the lung incontinuous mode, it is desirable to supply the lung with venousperfusion fluid having oxygen levels similar to those of the body. Gasexchanger 402 has a limited gas exchange capability, and at thephysiologic blood flow rate of 3-4 l/min., it is not able to removeenough oxygen from the blood to reduce the saturation levels to levelscorresponding to the body while the blood is being circulated throughthe lungs where is continually being reoxygenated. Therefore, to allowgas exchanger 402 to achieve physiologic levels of oxygen in the venousblood, the flow rate is reduced to about 1.5 l/min. In an alternativeembodiment, a flow rate intermediate between 1.5 l/min. and physiologicflow rates of 3-4 l/min. are used, with correspondingly higher oxygenlevels for the venous blood entering the lungs. In the describedembodiment, there is a trade-off between approximating physiologic bloodgas levels as the blood enters the lung on the one hand, and physiologicflow rates on the other. The trade-off may be reduced or eliminated byincreasing the gas exchange capability of the system. In one approach,multiple gas exchangers are used in series or in parallel in the lungperfusion circuit. In another approach, the gas exchanger's gas exchangecapability is increased by equipping it with a larger gas exchangesurface.

Continuous mode assessment is typically performed directly after thelungs have been kept in maintenance mode. The following alternateembodiment expedites the switchover from maintenance to continuous modeassessment. Initially, in maintenance mode, bellows 418 contain a fullvolume of maintenance gas, which would normally be flushed out duringseveral air ventilation cycles. Instead, a purge maneuver is performedto replace the entire contents of the bellows 418 with air. During thepurge, bellows valve 414 is open, and bellows 418 are fully compressedat a slow rate. During this compression, relief valve 412 is activelycontrolled to maintain the pressure near the PEEP level. At the end ofthis compression cycle, bellows valve 414 is closed, and bellows 418 isfully expanded, filling its entire volume with fresh air from checkvalve 416. One or more purge cycles may be performed to thoroughlyestablish the new gas composition.

Once the system is in steady state, the values of the perfusate oxygenlevels entering the lung and exiting the lung are measured, as indicatedin FIG. 34, step 3408. Perfusate samples can also be taken to confirmlevels of oxygen and determine other components of the perfusion fluid.In continuous assessment mode, the user assesses the gas exchangecapability of a lung by determining how much oxygen the lung cantransfer to the perfusate in each breath. This assessment is based onthe measured values of the oxygen levels in the perfusate entering thelung, and leaving the lung (3410). The assessment is calibrated usingvarious parameters, such as the fraction of oxygen in the gas that isventilating the lung. The standard measure of gas exchange capability isthe ratio between the partial pressure of oxygen in the blood in mm. ofmercury, PaO₂, and the fractional inspired oxygen value, FiO₂. In anormal resting person, this ratio is 100/0.21=450. A ratio below 300indicates a compromised lung, and a ratio less than 200 indicates acuterespiratory distress syndrome (ARDS). However, in order to validate thismeasure as an assessment tool in the OCS, several normalizingadjustments are required. One critical adjustment is for the level ofdeoxygenation of the blood before it enters the lung, PvO₂. In general,PvO₂ levels are higher in the OCS than in a person because of thelimited deoxygenation capability of the gas exchanger. Thus, for a givengas exchange capability of a lung, a higher PaO₂ is expected from a lungin the OCS's continuous assessment mode than in vivo.

Another measure of the gas exchange capacity of the lungs is thedifference between oxygen levels of blood entering the lungs, PvO₂, andthat of the blood leaving the lungs, PaO₂. In a normal person, the PvO₂level is about 40 mm Hg and PaO₂ is about 100 mm Hg, with a differencebetween outgoing and incoming oxygen levels of 60 mm Hg. On the OCS, thePvO₂ level may be 60 mm Hg, and a healthy lung may achieve a PaO₂ of 115mm Hg, with a PaO₂—PvO₂ value of 55 mm Hg, close to the correspondingvalue in vivo.

In order to validate measured continuous mode parameters as anassessment tool, several normalizing adjustments are required. Theseadjustments are based on factors such as ventilation parameters,hematocrit levels, blood flow rate, lung volume, altitude, andtemperature.

Sequential Assessment Mode

Sequential assessment mode is a second method of evaluating the lungs'gas exchange capability. In this mode, the lungs receive deeply venousperfusate oxygen levels that subject them to a different capability testthan that of continuous assessment mode.

Sequential assessment includes three phases: deoxygenation, hold, andreoxygenation. The deoxygenation phase removes oxygen from all theperfusate in the system. After the hold phase, the lungs thenreoxygenate the perfusate pool. The speed at which they achievereoxygenation is an indication of their gas exchange capability. FIG. 35shows the principal steps involved in performing a sequential assessmentof the lungs.

Deoxygenation phase 3502, 3504 is used to lower the oxygen content ofperfusion fluid 250. This is achieved by using both gas exchanger 402and lungs 404. To cause gas exchanger 402 to deoxygenate the blood,deoxygenation gas 500 is fed into it by setting gas selector valve 216to select deoxygenation gas, and opening gas exchanger valve 204.Although the gas exchanger can deoxygenate the blood on its own, theprocess is expedited by using the lungs and the ventilator. Toaccomplish this, the ventilator is configured to run as a rebreather, asin maintenance mode (see above), and trickle valve 212 injectsdeoxygenation gas 500 into the gas circuit. Within a few ventilatorcycles, the rebreathed gas in the gas circuit conforms to thedeoxygenation gas composition, i.e., about 6% CO₂ and 94% N₂, and thelungs act to deoxygenate the perfusion fluid circulating through them.In effect, the lungs are being used as a very effective gas exchanger tohelp deoxygenate the perfusate pool. As indicated in FIG. 35, step 3504,the deoxygenation phase continues until the perfusate oxygen falls to auser-defined threshold value, which is usually approximately 50-70%oxygen, and preferably about 60% oxygen.

In hold phase 3506, the deoxygenation process is halted by closing gasexchanger valve 204 and trickle valve 212 while perfusate continues toflow through the perfusion circuit. During this phase the perfusate poolis allowed to stabilize to a uniform level of deoxygenation. The timerequired to achieve uniformity may depend on the perfusate flow rate. Inan alternate embodiment, arterial and venous oxygen content levels aremonitored, and the hold phase is maintained until the levels becomeequal and constant over time. During the hold phase, ventilation ishalted, or, alternatively, the system performs one or more purge cycles(described above in the continuous assessment section) to prepare forthe reoxygenation phase. The purge cycle serves a useful role herebecause the gas in the gas circuit is being switched from deoxygenationgas to air, its polar opposite, and in order to start oxygenating theperfusion fluid immediately, the gas circuit needs to be filled with airat the outset.

In the final phase of sequential assessment mode, the oxygen-depletedperfusate pool is reoxygenated by ventilating the lungs with air oranother ventilation gas (step 3508). The ventilation is performed usingthe same method as described above for continuous assessment, with thedifference that gas exchanger valve 204 is kept closed. Thus in thereoxygenation phase of sequential assessment mode, the lungs are theonly source of gas exchange in the perfusion circuit (step 3510). Thetime taken for the lungs to reoxygenate the perfusate pool is the keyindicator of the lung gas exchange capability. The measuredreoxygenation time is the time for perfusion fluid 250 to go from ade-oxygenated state to a predetermined oxygenated level as measured byone or both of pulse oximeter probes 116 and 118 (step 3512). In analternative embodiment, blood samples are taken from one or more ofsampling ports 234, 236 and the saturation levels are measured by a labblood gas analyzer. The saturation at the oxygenation threshold level isset in the range of 90% to 100% and is preferably set at 93%.

The gas exchange capability of the lungs, as measured by the time takenfor the air-ventilated lungs to reoxygenate the blood from thedeoxygenation threshold level to the oxygenation threshold levelprovides a measure of the condition of the lungs (step 3514). Ingeneral, a healthy lung will be able to reoxygenate the perfusate poolin 4-5 breaths, which corresponds to a sequential assessment modereoxygenation time in the range of 45 to 90 seconds, and typicallyapproximately one minute. Validation of the reoxygenation time as anassessment tool may require normalization based on ventilationparameters, hematocrit, blood flow rate, lung volume, and altitude.

In an alternative embodiment of sequential mode assessment, a gas otherthan air is supplied to the inlet of check valve 416 during theoxygenation phase. For example, gas from devices that provide gas at 50%or 100% oxygen in a hospital setting can supply the ventilation gas. Inthis case, reoxygenation times are reduced, and to determine the lungs'gas exchange capability, the reoxygenation time measurements need to beappropriately calibrated.

Another method of assessing lung gas exchange capability duringsequential assessment mode is to measure the speed at which the lungsdeoxygenate perfusion fluid 250 during the deoxygenation phase. Theeffectiveness of the lungs in deoxygenating perfusion fluid 250 whilebeing ventilated with deoxygenation gas 500 provides an indication ofthe lungs' gas exchange capability.

An advantage of sequential assessment mode is that physiologic bloodflow rates of 3-4 l/minute can be used because, during reoxygenation,gas exchange is being performed only by the lung. Since the gasexchanger is not involved, there is no need to limit blood flow.

Lung Ventilator Pneumatic Circuit

The lung ventilator pneumatic circuit provides a means of controllingbellows valve 414 and relief valve 412 for controlling various modes ofventilation. It also controls gas flow to blood gas exchanger 402 andthe lungs. Pneumatic control offers several advantages, including theability to open and close valves at different rates, the availability ofinexpensive, disposable pilot valves, the ability to isolate lungconsole module 200 from the valves carrying gases exposed to the lung,and providing a convenient and modular interface for connecting anddisconnecting disposable lung perfusion module 400 to console module200.

Software running on console module controller 202 controls pneumaticcontrol module 208, which in turn controls relief valve actuator 207 andbellows valve actuator 210. FIG. 5 a shows the components of thepneumatic circuit in lung console module 200, and how the circuitconnects to lung perfusion module 400. The components corresponding topneumatic control module 208 as indicated on FIG. 1 are identified bythe dotted line in FIG. 5 a. Table 1 is a list of the pneumatic circuitparts according to the described embodiment.

TABLE 1 Ref. No. in FIG. 5a Part Description 216 V1: Gas Selector Valve,3 way 15 SLPM, 25 PSI MAX Line Pressure, ASCO AL2312, 0.65 W, 0.055″(4.3 PSI drop @ 15 SLPM) 204 V2: Blood Gas Valve, 2 way NC, 10 SLPM, 25PSI MAX Line Pressure, ASCO AL2112, 0.65 W, 0.055″ (2 PSI drop @ 10SLPM) 212 V3: Re-breather Gas Valve, 2 way NC, 5 SLPM, 25 PSI MAX LinePressure, ASCO AL2112, 0.65 W, 0.55″ (0.6 PSI drop @ 5 SLPM) 210 V4:Bellows Pilot Valve, 3 way, 1.5 SLPM, 3 PSI MAX Line Pressure, ASCOAL2312, 0.65 W, 0.55″ (2.5 cm H2O drop @ 1.5 SLPM) 207 V5: Relief PilotLinear Pressure Control, Variable Orifice (0.020″ to 0.170″ Using LinearStepper motor, Haydon 20544-05-018, 2.5 W (0.1 to 70 cm H2O drop at 1.8to 2.5 SLPM) 414 V6: Bellows Valve, Instrument Industries BE 30-115-BL412 V7: Relief Valve, Instrument Industries BE 30-115-BL 205 R1: BloodGas Restrictor, Bird Precision RB 82304 BR (SA087)- 24054, 10.8 SLPM @25 PSI, 0.0290″ 213 R2: Ventilator Gas Restrictor, Bird Precision RB82304 BR (SA087)- 24060, 5.7 SLPM @ 25 PSI, 0.0210″ 608, 616 C1, C2:Check Valve, 1 PSI, McMaster Carr 6079T54 606 F1: Filter, McMaster Carr8991T312 602 P1: Assessment Gas Connector Colder PMC1602 624 P2:Perfusion Module Gas Connector, Colder SM1702 (six lumen) 604 P3:Maintenance Gas Connector, Colder PMC1702 206 X1: Airway Pressure (PEEP,PAWP sensing) 620 X2: Relief Valve Pilot Pressure (for controllingrelief valve) 612 A1: Air Pump, 1.5 SLPM @ 3 PSI, Hargraves H103-11_B.1F28E1.A12VDC, 3 W

The pneumatic circuit of lung console module 200 connects to lungperfusion module 400 via gas connectors 624, 626. FIG. 5 b shows a frontview of connector 624, showing a six-lumen connector, with gas lines630, 632, 634, 636, and 638 providing connections to gas exchanger 402,the rebreathing gas circuit, bellows valve 414, relief valve 412, andairway pressure respectively. The connector permits rapid removal andhookup of disposable lung perfusion module 400 to lung console module200.

Maintenance gas 220 and deoxygenation gas 500 are connected to gasselector switch 216 by connectors 604 and 602 respectively. Gas selectorswitch 216 selects which gas to pass through gas exchanger valve 204 andtrickle valve 212. The control of trickle valve 212 is synchronized withthe ventilation cycle; the valve is opened during the inhalation phase,as described above for FIG. 6, and is kept open for long enough toobtain the desired average gas flow rate. The rate of flow to gasexchanger 402 is controlled by pulse width modulation of the controlvalve 204 from valve 216. Valves 204 and 212 effect control of the gasflow rate using orifice restrictors 205 and 213 respectively.

Bellows valve 414 and relief valve 412 are both capable of high flowrates, such as 1 liter/second. In the case of bellows valve 414, thehigh flow rate capability allows non-restrictive, free gas flow betweenthe lungs and the bellows during inhalation and exhalation. In the caseof relief valve 412, the high flow rate capability allows the lungs toexhale rapidly to the PEEP value. In the described embodiment, bellowsvalve 414 and relief valve 412 are commercially available high flow ratepilot valves. Applying positive pressure to the pilot valve diaphragmcloses the valve; negative pressure fully opens the valve.

The lower section of FIG. 5 a shows how pilot valve control is achievedfor bellows valve 414 and relief valve 412. Air pump 612 runsconstantly, providing an approximately constant flow of air through thepump. The pump draws in ambient air through inlet filter 606, and checkvalve 608. This flow creates a pressure difference across check valve608 of about 1 PSI, or 70 cm of H₂O, which results in a pressure ininlet reservoir 610 pressure of −70 cm of H₂O relative to ambientpressure. Inlet reservoir 610 and outlet reservoir 614 serve to filterthe uneven pressure ripple from reciprocating pump 612. After passingthrough outlet reservoir 614, the outlet of air pump 612 flows throughsecond 1 PSI check valve 616. Thus the pressure in outlet reservoir 614is 70 cm of H₂O above ambient, provided relief valve actuator 207 isopen to ambient pressure.

Bellows valve 414 is controlled as follows. Bellows valve actuator 210can be connected to either inlet reservoir 610 or outlet reservoir 614.To open bellows valve 414, actuator 210 is connected to inlet reservoir610, which is at −70 cm of H₂O. Actuator 210 causes this negativepressure to be transferred via pneumatic line 634 to the diaphragm ofbellows valve 414. The negative pressure on the diaphragm causes valve414 to open. To close bellows valve 414, actuator 210 is connected tooutlet reservoir 614 at +70 cm of H₂O, causing positive pressure to beapplied to the valve diaphragm, which shuts off the valve.

Relief valve 412 is controlled by applying a positive pressure to thevalve's diaphragm, but in this case a controllable pilot gas pressure ofthe valve is used to set the PEEP in the perfusion module gas circuit.Relief valve 412 remains open, and gas in the ventilation loop is ventedto the outside, as long as the pressure in the ventilation loop isgreater than the pilot pressure on the valve's diaphragm. When thepressure in the ventilation loop falls below that of the pilot pressure,relief valve 412 closes. Thus by setting the pilot pressure to thedesired PEEP value, the relief valve allows gas to vent from the gasloop until the pressure falls to the desired PEEP level, and then itshuts off. In alternate embodiments, the PEEP valve is actuated withhigher or lower pilot pressure to effect the exhalation rate through thevalve.

Variable control of pilot pressure in relief valve 412 is achieved byusing linear stepper motor 618 in conjunction with a variable orificevalve in relief valve actuator 207. Stepper motor 618 controls the sizeof the opening of the variable orifice valve. The smaller the opening ofthe orifice, the more resistance to airflow, the less airflow from airpump 612 escapes to the ambient air, and the higher the pressure betweencheck valve 616 and relief valve actuator 207. This pressure istransmitted to relief valve 412 via pneumatic line 636. This enables theprocessor to obtain an empirically calibrated relationship betweenrelief valve pilot pressure and PEEP. The actual pilot pressure ismeasured by relief pilot valve pressure sensor 620; this is monitored bylung console module processor 202, which also receives measurements ofairway pressure from airway pressure sensor 206. In an alternateembodiment, the pilot pressure measurement is used to control the pilotpressure by comparing the actual pilot pressure to the desired pilotpressure and changing the stepper motor position to equalize them.

System Information Display and System Monitoring

OCS monitor 300 is the main input and output interface for the systemoperator. LCD 304 displays real time measurements and derived values ofinterest for the perfusion solution and for the gas loop. It alsodisplays the status of other OCS subsystems, such as battery levels andgas tank levels. The nature of the information displayed on OCS LCDdisplay 402 is explained next. Following this, screen shotscorresponding to maintenance mode, continuous assessment mode, andsequential assessment mode are described.

FIG. 11 is an exemplary screen shot of LCD 304; the screen shotcorresponds to maintenance mode. LCD 304 includes a display area 1102showing real time trace 1104 of the ventilation pressure at the entranceto the lungs, as measured by airway pressure sensor 206. The displayalso includes numerical values 1106, 1108 of the ventilation pressurereadings; numerator 1106 is the peak pressure value, which is themaximum pressure sampled over the entire ventilation cycle. Denominator1108 is the PEEP value for the last respiration cycle, which is derivedby sampling the airway pressure at the end of the expiratory time, i.e.,just before inhalation for the next cycle begins. Since PEEP is definedas the pressure right at the end of the respiration cycle, it does notnecessarily correspond to the minimum pressure in the cycle. Lowerpressures may occur in the system if, for example, the system overshootsor undershoots as it attempts to reach the set PEEP value. Additionalnumerical values 1110, 1112, and 1114 show the configured set point (sp)values, i.e., the values selected by the user. The display of thesevalues helps the user compare the displayed actual values of respiratorypressure with the configured desired values. Value 1110 shows the setpoint value for PAWP, which is an absolute upper pressure limit, orclamp, on the respiratory pressure. Generally, the ventilation pressurewaveform is below the PAWP limit at all times. As described above, thePEEP set point 1112 corresponds to the desired respiratory pressure atthe end of a respiration cycle, after exhalation is complete and justbefore the inhalation pressure ramp of the next cycle starts. Value 1114shows I:E, which is the ratio of the respiration cycle time associatedwith inspiration and exhalation. The inspiration period includes boththe inhalation time corresponding to flowing gas into the lungs, i.e.,inhalation ramp 654 (FIG. 6), as well as the plateau time 658. ThusI:E=(inspiratory time+plateau time):expiratory time. The system derivesthe I:E value from the configured inspiratory time, plateau time, andrespiration rate.

Display area 1116 of LCD 304 shows a real time trace 1118 of pulmonaryarterial pressure (PAP) as measured by pressure sensor 115. Alsodisplayed are PAP numerical values showing a snapshot of key values:peak or systolic pressure 1120, valley or diastolic pressure 1122, andmean perfusate pressure 1124 at the pulmonary artery feed at the lung.

In lower display area 1126, time averaged graph 1128 of PAP isdisplayed, together with numerical value 1130 displaying the average PAPvalue. The choice of what to display on LCD 304 is under operatorcontrol. FIG. 12 shows configuration menu 1202, with maintenance tab1204 selected. In this mode, the operator can select what information todisplay in each of middle graphic area 1116 and bottom graphic area1126. Upper graphic frame 1102 is also configurable (not shown). Theconfiguration menu maintenance tab also provides the ability to set theaverage flow rate of maintenance gas 220 through trickle valve 212, aswell as control the perfusate temperature. Other parameters of the lungventilator can also be controlled via the maintenance tab menu.

LCD 304 displays a number of additional numerical values that providethe system user with a snapshot of the lung condition and OCSparameters. Displayed value 1160 shows pulmonary flow (PF) of perfusateinto lungs 404 as measured by flow rate sensor 114. Displayed value 1162shows pulmonary vascular resistance (PVR), which is a measure of theresistance exerted by lungs 404 to the flow of perfusate. In general, alower PVR value is preferable because it indicates a less restrictiveflow of the perfusate through the vasculature of lungs 404. In thedescribed embodiment, favorable values of PVR are in the range of 200 to400 dynes. Displayed value 1164 shows venous saturation hemoglobincontent, SvO₂ of perfusion fluid 250, as measured by oxygen sensor 116.Similarly, displayed value 1166 shows arterial saturated hemoglobincontent, SaO₂ of perfusion fluid 250, as measured by oxygen sensor 118.In certain embodiments, icons indicating SvO₂ and SaO₂ alarms aredisplayed adjacent to displayed values 1164 and 1166 respectively, forsignaling the operator if either saturated hemoglobin value falls belowan operator preset threshold. Such alarms may be implemented for anyparameter measured, calculated or displayed. Displayed value 1168 showsthe hematocrit (HCT) level of perfusion fluid 250 and, optionally, anHCT alarm indicator for signaling the operator if the HCT level 1168falls below an operator preset threshold. Displayed value 1170 indicatesthe temperature (Temp) 1170 of perfusion fluid 250 as it flows away fromheater assembly 230. Displayed value 1170 may also include a Temp alarmindicator which signals in response to Temp 1170 being outside of anoperator preset range. Temperature set point 1171 selected by theoperator is also shown. Display area 1172 shows a numerical reading ofthe ventilation rate measured in breaths per minute (BPM) of a gasdelivered to lungs 404 via the tracheal interface 1024. The BPM value isderived from one or more inputs, including readings from airway pressuresensor 206. In addition, BPM set point 1173, as selected by theoperator, is displayed. Displayed value 1174 shows the tidal volume(TV), the volume of gas flowing into lungs 404 during each inhalation.

LCD 304 further includes circulatory pump indicator 1138 showing astatus of the system's circulatory pump. Display area 1176 shows anorgan type indicator 1140 that indicates which organ is being perfusedand an organ mode indicator 1142 that indicates what mode of operationis being used. For example, an “M” is used to indicate maintenance mode.SD card indicator 1144 shows whether an SD card is used to store datacollected during organ perfusion. Display area 1146 includes gas tankdiagram 1178 that graphically indicates remaining maintenance gasvolume. Display area 1146 also includes one or more numerical displayedvalues 1180 indicating a flow rate of the gas in the gas supply alongwith the time remaining for which the gas is delivered to lungs 404during perfusion. This remaining time may be calculated based on theremaining gas volume and the gas flow rate. Display area 1148 showsgraphical representation 1182 of the degree to which each of thebatteries of OCS console 100 are charged. Battery status symbol 1184indicates that the batteries whose status are represented by graphicalrepresentation 1182, are used to power OCS console 100. Display area1150 shows graphical representation 1186 of the degree to which thebattery that powers the user interface is charged. Display area 1188identifies whether the OCS monitor 300 is operating in a wirelessfashion.

In other embodiments, display screen 304 also shows FiO₂ and FiCO₂concentrations, which are fractional concentrations of oxygen and carbondioxide, respectively, measured at the entrance to the trachea. Displayscreen 406 can additionally show readings of weight and elasticity oflungs 404, PH of perfusion fluid 250 circulating through the lungs 1004,partial pressures of gas components in perfusion fluid 250, and PEEPlevels.

The information displayed on OCS monitor LCD 304 is now described inrelation to the mode of operation of OCS 1000. As stated above, FIG. 11shows a lung in maintenance mode; the values displayed in the figure areto be taken as exemplary. As indicated along the left column of data,the perfusate flow rate is 1.46 l/min, a value lower than physiologiclevels, but sufficient to nourish the lung. As shown in the figure, SvO₂value 1164 is 92.4% and SaO₂ value 1166 is 92.2%. These levelscorrespond to equilibrium between maintenance ventilation gas 220 andthe perfusate gases. The difference between arterial and venous oxygenlevels is caused by oxygenation from air entering the organ chamber(tending to increase SaO₂), and from the small consumption of oxygen bythe lungs (tending to decrease SaO₂). The balance between these factorscan cause SaO₂ to be higher or lower than SvO₂. In general, oncemaintenance mode is fully established, the oxygen saturation values ofthe perfusate as it enters and exits the lungs are stable and equal toeach other within about ±5%. As oxygen is consumed by the lungs it iscontinually replaced by trickling in maintenance gas 220 via tricklevalve 212 during each ventilation cycle. Graph 1104 shows theventilation pressure over time; the pressure rises when the bellowspushes air into the lungs, and diminishes to the desired PEEP value atthe end of exhalation. The graph shows the pressure profile over themost recent ventilation cycles; display area 1172 shows that the lungsare being ventilated at a rate of 10 breaths per minute. Graph 1118shows real time PAP corresponding to the most recent ventilation cycles.The curve shows periodic peaks that correspond to the pulse of thecirculatory pump 226. Graph 1128 shows the PAP trend. Numerical value1170 shows that the perfusate temperature is measured to be 35.0 degreescentigrade, and is equal to the set point value shown in numericaldisplayed value 1171. Such a sub-physiologic temperature level isselected to reduce the metabolic rate of lungs 404 during preservation.One advantage of a lower metabolic rate is the ability to lower themaintenance gas requirement of lungs 404, thereby permitting them to bepreserved for a longer time with a finite volume of maintenance gas 220.

FIG. 13 is an exemplary screen shot of OCS monitor LCD 304 when thesystem is in continuous assessment mode. Respiration graph 1302 andnumerical values 1304 are similar to those shown in FIG. 11 formaintenance mode. However, PAP graph 1306 and numerical values 1308 showan average pressure of 13 mm Hg, which is considerably higher than thecorresponding 10 mm Hg pressure during maintenance mode. The higherpressure is required to achieve a higher flow rate of perfusion fluidthrough the lung, so as to allow testing of the lung's gas exchangecapability. The screen shows flow rate 1310 at 2.93 liters/minute. Inthis mode, gas exchanger 402 deoxygenates perfusion fluid 250 to SvO₂level 1312 of 82.3%. The lungs reoxygenate the blood using airventilation, achieving SaO₂ level 1314 of 96.1%. Hematocrit level 1316is 30%, and perfusate temperature 1318 is maintained at about 37.1degrees C., the physiologic value. The respiration rate displayed value1320 shows a rate of 12 breaths per minute, corresponding to that of aresting person. Tidal volume displayed value 1322 shows a value of 700ml, well within the physiologic range. OCS status display 1324 shows agraphic of the lungs, indicating that OCS 1000 is preserving a lung, andthe letters A and C, indicating that the system is in continuousassessment mode.

Having described the system display corresponding to maintenance modeand continuous assessment mode, we now describe how the deoxygenation,hold, and oxygenation phases of sequential assessment mode are displayedon LCD 304. FIG. 14 is an exemplary screen shot of LCD 304 when thesystem is in deoxygenation phase. In this phase, deoxygenation gas 500is passed through gas exchanger 402 and into the ventilation loop intolungs 404. Oxygen levels in perfusion fluid 250 drop rapidly, sinceoxygen is being removed by gas exchange both in lungs 404 and gasexchanger 402. Graphs 1406 and 1408 show the values of SaO₂ and SvO₂respectively over a period of about one minute after the start of thedeoxygenation phase. During this time, the values drop from the lownineties down to a SaO₂ value of 64.9% and a SvO₂ value of 59.9%, asindicated at the right end of graphs 1406 and 1408 and in numericaldisplayed values 1412 and 1410 respectively. Thus, perfusate saturationlevels well below the physiologic range can be achieved rapidly,especially when lungs 404 supplement the gas exchange capability of gasexchanger 402. Ventilation pressure graph 1402 and PAP levels remainsimilar to those of continuous assessment mode. System status display1414 indicates lung assessment—deoxygenation phase, with the letters A,D. Also displayed are the user-determined values for the deoxygenationtermination threshold 1416, oxygenation phase lower threshold 1418, andoxygenation phase upper threshold 1420.

FIG. 15 shows an exemplary user interface for setting sequentialassessment parameters. Configuration mode 1502 is selected by pressingmenu button 306 on OCS monitor 300. The user enters and applies settingsin sequential submode settings menu 1504. Listed are user-settablevalues for hold time 1506, which is the time between the end of thedeoxygenation phase and the start of the oxygenation phase, anddeoxygenation termination threshold 1508, which is the target lowestlevel of oxygen content in perfusion fluid 250, i.e., the system stopsdeoxygenation if/when this level is reached. The user also sets valuesfor oxygenation lower threshold 1510, the target value for perfusateSvO₂ in the oxygenation phase, and oxygenation upper threshold 1512, thetarget value for perfusate SaO₂ in the oxygenation phase.

After deoxygenation mode, the system enters hold phase. FIG. 16 is anexemplary screen shot corresponding to hold phase. The purpose of holdphase is to allow the oxygen levels in perfusion fluid 250 to becomeuniform. The extent to which this is achieved can be seen in graphs 1602and 1604, showing the time-changing values of SaO₂ and SvO₂ in perfusionfluid 250. The flat parts of both curves indicate the saturation levelsare constant, and the closeness of the graphs for SaO₂ and SvO₂ indicateuniformity of the saturation levels on each side of lungs 404. Numericaldisplayed values 1608 and 1606 indicate values of SaO₂ and SvO₂respectively. As shown in FIG. 16, the measured values of SaO₂ and SvO₂about one minute into the hold phase are 58.9% and 58.0% respectively,i.e., very close to each other.

In the third phase of sequential assessment mode, perfusion fluid 250 isreoxygenated by lungs 404, while being ventilated with air. The gasexchange capability of the lungs is related to the time taken to fullyreoxygenate the perfusate pool. FIG. 17 is an exemplary screen shot ofthe system in the reoxygenation mode. Graphs 1702 and 1704, show thetime-changing values of SaO₂ and SvO₂ in perfusion fluid 250. Towardsthe left side, the graphs show the initial decline of the oxygen levelsduring the deoxygenation phase described above. The flat portions of thecurves in the middle of the graphs correspond to the hold phase, whichlasts for about one minute. At the right end of the hold phase flatportion of the graph, oxygenation mode begins. Shortly after switchingto oxygenation mode, the graphs start rising, which indicates oxygen gasexchange via the lungs into perfusion fluid 250. Graphs 1702 and 1704and numerical displayed values 1708 and 1706 show that about 80 secondsinto the oxygenation phase, SaO₂ and SvO₂ levels have climbed to 94.6%and 85.2% respectively. The time taken to reach a user-selectedthreshold oxygenation level in perfusion fluid 250 is shown in numericaldisplayed value 1710.

Additional screens for configuring OCS 1000 are now described. FIG. 18shows the assessment tab 1802 of configuration menu 1202. This screenenables the user to determine what information is to be shown in middlegraphic frame 1116, in the bottom graphic frame 1126, to set temperatureset point 1171, and to choose which assessment mode toperform—sequential or continuous. Tab 1802 also allows the user toselect the ventilator setting menu, as well as the sequential assessmentsubmode settings.

FIG. 19 shows ventilator settings menu 1902. Respiration rate 1904selects the number of ventilation cycles per minute. Tidal volume 1906determines the volume of gas inhaled by the lung in each breath.Inspiratory time 1908 is the duration of the inhalation phase. Peakairway pressure (PAWP) 1912 is the maximum allowed gas pressure duringthe breathing cycle; it occurs while gas is being pushed into lungs 404by bellows 418. PEEP 1914 controls the pressure in the lung whenexhalation is complete.

FIG. 20 shows lung tab 2002, which allows the user to set lung mode 2004to maintenance or assessment, allows ventilator control 2006 to beswitched on or off, and provides a link 2008 to lung setting submenu.FIG. 21 shows system tab 2102, which allows the user to set time anddate, language, and perform other system actions. Other configurationtabs and associated menus can be added based on the needs of users.

Organ Care System Console Module

FIG. 22 is an overall view of OCS console 100 showing the single use,disposable lung perfusion module in a semi-installed position. Asbroadly indicated in FIG. 22, single use disposable lung perfusionmodule is sized and shaped to fit into OCS console 100, and to couplewith it. Overall, the unit has a similar form to the organ care systemdescribed in U.S. patent application Ser. No. 11/788,865. Removable lungperfusion module 400, is insertable into OCS console 100 by means of apivoting mechanism that allows module 400 to slide into the organconsole module from the front, as shown in FIG. 22, and then pivottowards the rear of the unit. Clasp mechanism 2202 secures lungperfusion module 400 in place. In alternative embodiments, otherstructures and interfaces of lung perfusion module 400 are used tocouple the module with OCS 100. When secured in place, electrical andoptical connections (not shown) provide power and communication betweenOCS console 100 and lung perfusion module 400. Details of the electricaland optical connections are described in U.S. patent application Ser.No. 11/246,013, filed on Oct. 7, 2005, the specification of which isincorporated by reference herein in its entirety. A key component oflung perfusion module 400 is organ chamber 2204, which is described indetail below. Battery compartments 2206 and maintenance gas cylinder 220(not shown) are located in the base of the OCS console 100. OCS console100 is protected by removable panels, such as front panels 2208. Justbelow lung perfusion module are perfusate sampling ports 234 and 236.Mounted on top of OCS console 100 is OCS monitor 300.

FIG. 23 is a side view of OCS console 100. LA sampling port 234 and PAsampling port 236 provide means for removing perfusate samples, or forinjecting chemicals into perfusion fluid 250. Maintenance gas tankregulator 222 and gauge 2304 are visible in OCS console 100 base. Alsovisible is one way inflow valve 2306, which is attached to the reservoirand connected to the dome of the perfusate pump.

Additional system components are visible in FIG. 24, which is a frontview. Bellows 418 is located just above the OCS console module base, andis driven by mechanical actuator arm 2402 connected to ventilator unit214 in lung console module 200. Mechanical motion of actuator arm 2402causes bellows 418 to compress and expand, which drives the gas flowinto and out of lungs 404 during a breathing cycle. Gas exchanger 402 islocated above bellows 418. In the described embodiment, gas exchanger402 is a Novalung oxygenator. Perfusate fluid line 2404 connects fluidpump 226 (not shown) and heater 230 (not shown). Just below organchamber 2204, reservoir 224 collects perfusion fluid, and connects viadrain 2408 to pump 226 for recirculation through the system.

In FIG. 25, the walls of OCS console 100 have been omitted so as toreveal additional internal components of the system. Maintenance gas 220is stored in a horizontally disposed cylinder, feeding maintenance gas220 to the system when needed via regulator 222. Lung perfusion module400 is shown in the installed vertical position. Adjacent to bellows 418is bellows drive plate 2502, which mates with a flat disk at the end oflinear actuator 2402 (not shown).

FIG. 26 is a view of OCS console 100 without disposable lung perfusionmodule 400. Visible are ventilator module 214 and mechanical actuatorarm 2402. Other components (not shown) of lung console module 200 arehoused within the module mounted along the left side wall of the OCSconsole 100. These components are shown in FIG. 1 within lung consolemodule 200, and include console module controller 202, gas exchangervalve 204, airway pressure sensor 206, relief valve actuator 207,pneumatic control module 208, bellows valve actuator 210, trickle valve212, ventilator 214, gas selector switch 216, and power converter 218.Pneumatic connector 624 provides rapid hook-up to matching lungperfusion module connector 626. This convenient connection provides gasconnection to gas exchanger 402 and also to the gas loop between lungs404 and bellows 418. Connectors 624 and 626 also provide pneumaticcontrol connections between lung console module 200 and lung perfusionmodule 400 to control bellows valve 414, relief valve 412, and receivepressure data for air sensor 206.

FIG. 27 is a front view of lung perfusion module 400. Organ chamber 2204includes a removable lid 2820 and housing 2802. Sampling ports,including LA sampling port 234 and PA sampling port 236 are visiblebelow organ chamber 2802. Gas exchanger 402, bellows 418, and bellowsplate 2502 are also visible in the figure.

We now describe the circulation path of the perfusate, which was firstdescribed in connection with FIG. 2, in terms of the components of lungperfusion module 400. Mounted below organ chamber 2204 are perfusatereservoir 224, which stores perfusate 250. The perfusate exits throughone-way inflow valve 2306, line 2702, and pump dome 2704 to pump 226(not shown). The perfusate is pumped through perfusate fluid line 2404through compliance chamber 228, and then to perfusate heater 230. Afterpassing through heater 230, the perfusate passes through connecting line2706 to gas exchanger 402. The perfusate exits gas exchanger 402 throughconnecting line 2708 to the interface with the pulmonary artery. Afterflowing through the lung and exiting via the pulmonary vein and the leftatrium, the perfusate drains through from the base of organ chamber2204, as described below. These drains feed the perfusate to reservoir224, where the cycle begins again.

Having described OCS console 100 and lung perfusion module 400, we nowdescribe organ chamber 2204. FIG. 28 shows an exploded view of thecomponents of organ chamber 2204. Base 2802 of chamber 2204 is shapedand positioned within lung perfusion module 400 to facilitate thedrainage of the perfusion medium. Organ chamber 2204 has two drains,measurement drain 2804, and main drain 2806, which receives overflowfrom the measurement drain. Measurement drain 2804 drains perfusate at arate of about 0.5 l/min, considerably less than perfusion fluid 250 flowrate through lungs 404 of between 1.5 l/min and 4 l/min. Measurementdrain leads to oxygen probe 118, which measures SaO₂ values, and thenleads on to reservoir 224. Main drain 2806 leads directly to reservoir224 without oxygen measurement. Oxygen probe 118, which is a pulseoxymeter in the described embodiment, cannot obtain an accuratemeasurement of perfusate oxygen levels unless perfusion fluid 250 issubstantially free of air bubbles. In order to achieve a bubble-freecolumn of perfusate, base 2802 is shaped to collect perfusion fluid 250draining from lungs 404 into a pool that collects above drain 2804. Theperfusate pool allows air bubbles to dissipate before the perfusateenters drain 2804. The formation of a pool above drain 2804 is promotedby wall 2808, which partially blocks the flow of perfusate frommeasurement drain 2804 to main drain 2806 until the perfusate pool islarge enough to ensure the dissipation of bubbles from the flow. Maindrain 2806 is lower than measurement drain 2804, so once perfusateoverflows the depression surrounding drain 2804, it flows around wall2808, to drain from main drain 2806. In an alternate embodiment of thedual drain system, other systems are used to collect perfusion fluidinto a pool that feeds the measurement drain. In some embodiments, theflow from the lungs is directed to a vessel, such as a small cup, whichfeeds the measurement drain. The cup fills with perfusion fluid, andexcess blood overflows the cup and is directed to the main drain andthus to the reservoir pool. In this embodiment, the cup performs afunction similar to that of wall 2808 in the embodiment described aboveby forming a small pool of perfusion fluid from which bubbles candissipate before the perfusate flows into the measurement drain on itsway to the oxygen sensor.

Lungs 404 are supported by support surface 2810. The surface is designedto support lungs 404 without applying undue pressure, while anglinglungs 404 slightly downwards towards the lower lobes to promote easydrainage of the perfusate. Support surface includes drainage channels2812 to collect and channel perfusate issuing from lungs 404, and toguide the perfusate towards drain 2814, which feeds perfusate directlyto the blood pool for measurement drain 2804. To provide additionalsupport for the lungs, lungs 404 are wrapped with a polyurethane wrap(not shown) when placed on support surface 2810. The polyurethane wrapanchors lungs 404, helps keep the lungs in a physiologic configuration,and prevents the bronchi from being kinked and limiting the total volumeof inflation. The wrap provides a smooth surface for the exterior of thelung to interface with organ chamber 2204, reducing the risk of thechamber applying excessive pressure on any part of lungs 404, whichmight cause undesirable hemorrhaging. The polyurethane wrap is markedwith a series of lines indicating how much volume is being wrapped. Thedesired volume of wrapped lung can be determined by an empiricalrelationship between lung size and the weight of the donor. Thepolyurethane wrap has a series of small holes for draining perfusatethat collects around lungs 404. The perfusate is collected by drainagechannels 2812 in support surface 2810, which channel the perfusate todrain 2814.

The top of organ chamber 2204 is covered with a sealable lid thatincludes front piece 2816, top piece 2820, inner lid with sterile drape(not shown), and sealing piece 2818 that seals front piece 2816 to toppiece 2820. In an alternate embodiment, the organ chamber includes adouble lid system similar to that disclosed in connection with the heartpreservation chamber described in U.S. patent application Ser. No.11/245,957, which is incorporated herein in its entirety. The double lidsystem includes an outer lid, an intermediate lid, a flexible membraneand sealing frames between the lids and the organ chamber walls. Themembrane is preferably transparent, and permits a medical operator totouch/examine the lungs indirectly through the membrane, or apply anultrasound probe to the lungs through the membrane, while maintainingthe sterility of the chamber. The outer lid opens and closes over theintermediate lid independently of the intermediate lid. Preferably theouter lid is rigid enough to protect lungs 404 from physical contact,indirect or direct. The outer lid and the chamber may be made from anysuitable polymer plastic, for example polycarbonate.

Covering the organ chamber serves to minimize the exchange of gasesbetween perfusion fluid 250 and ambient air, and helps ensure that theoxygen probes measure the desired oxygen values, i.e., valuescorresponding to perfusate exiting the lungs via the LA (SaO₂), andentering the lung via the PA (SvO₂). The closing of organ chamber 2204also serves to reduce heat loss from lungs 404. Heat loss can beconsiderable because of the large surface area of the lungs. Heat losscan be an important issue during transport of the lungs when OCS 1000may be placed into relatively low temperature environments, such as avehicle, or the outdoors when moving OCS 1000 into and out of a vehicle.Furthermore, prior to transplantation, OCS 1000 may be temporarilyplaced in a hospital holding area or in an operating theater, both ofwhich typically have temperatures in the range of 15-22 degrees C. Atsuch ambient temperatures, it is important to reduce heat loss fromorgan chamber 2204 in order to allow heater 230 to maintain the desiredperfusate (and lung) temperature of 35-37 degrees C. Sealing the lungsin the organ chamber 2204 also helps to maintain uniformity of thetemperature through lungs 404.

FIG. 29 is a right side view of organ chamber 2204 with the coverremoved so as to show support surface 2810. Perfusate drainage channels2812 and drain 2814 carry perfusate to housing 2802. Also shown aretracheal cannula 700 and tracheal cannula connector 710 for connectionto OCS 1000 gas loop. Above tracheal cannula 700 is PA cannula 850 withdouble connection tubes 852 and 854 at 90 degrees, as illustrated inFIG. 8. Remotely vented pressure sensor 115 (not shown) is connected tothe perfusate flow at the point of entry from the PA cannula into lungs404 by means of connector 806, pressure transducer conduit 2902, andpressure transducer cable 2904. In FIG. 30, which is a left side view oforgan chamber 2804, tracheal cannula 700 is clearly displayed. Trachealcannula 700 is secured to the wall of housing 2802 by means of locknut708. Adjacent to locknut 708, flexible urethane tubing 706 projects intohousing 2802 of organ chamber 2204, leading to silicone-coveredconnector 704, which connects to the trachea.

Use Models

An exemplary model for using the organ care system described above forlung transplantation is described next with reference to FIGS. 31 and32.

The process of obtaining and preparing the lungs 404 for cannulation andtransport begins by providing a suitable organ donor at step 3100. Theorgan donor is brought to a donor location, whereupon the process ofreceiving and preparing the donor lungs 404 for cannulation andtransport proceeds down two intersecting pathways. The pathwaysprincipally involve preparing OCS 1000 to receive donor lungs 404 andthen transporting lungs 404 via OCS 1000 to a recipient site. Inparticular, pathway 3102 includes exsanguinating the donor, arrestingthe donor's heart, and preparing lungs 404 for cannulation into OCS1000. In particular, in the exsanguination step 3104, the donor's bloodis removed and set aside so it can be used to perfuse lungs 404 duringtheir maintenance on the OCS 1000. After the donor's blood isexsanguinated, the donor heart is injected in step 3106 with acardioplegic solution to temporarily halt its beating in preparation forharvesting lungs 404.

After the donor's heart is arrested, a pneumoplegia solution isadministered to the lungs at step 3108 before lungs 404 are explantedfrom the donor at step 3110 and prepared for loading onto OCS 1000 atstep 3112.

With continued reference to FIG. 31, after the lungs 404 are explantedfrom the donor's body, they are instrumented onto OCS 1000 at step 3124by insertion into the lung chamber 2204 and cannulation at theappropriate perfusion fluid and gas loop interfaces as described above.

According to other illustrative embodiments, the lungs 404 can betransferred directly from the donor to OCS 1000 without the use ofcardioplegia. In one particular implementation, the donor's lungs 404are removed without the donor's heart being arrested and aresubsequently instrumented into OCS 1000 for maintenance.

During the preparation of the lungs 1004 via path 3102, OCS 1000 isprepared through the steps of path 3114 so it is primed and waiting toreceive lungs 404 for cannulation and transport as soon as the lungs 404are prepared. In particular, OCS 1000 is prepared in pathway 3114through a series of steps including providing single use lung perfusionmodule 400 (step 3116), priming OCS 1000 with a maintenance solution(step 3118), filtering the blood from the donor and adding it toreservoir 224 (step 3120), and circulating and warming the perfusatewithin OCS 1000 (step 3122). In certain embodiments, perfusion fluid 250includes whole blood. In certain embodiments, perfusion fluid 250 ispartially or completely depleted of leukocytes. In certain embodiments,perfusion fluid 250 is partially or completely depleted of platelets, orincludes a blood plasma substitute and is packed with red blood cells.In certain embodiments, perfusion fluid additives include prostaglandinE, Prostacycline, dextran, isuprel, flolan and nitric oxide donors areadded while epinephrine is removed. The additives may be generallyselected from antimicrobials, vasodilators, and anti-inflammatory drugs.The additives may be delivered to the system 1000 via ports 234, 236coupled to the reservoir 224, or via an interface in tracheal cannula700 through a nebulizer or a bronchoscope.

At step 3126, OCS 1000 is selected to operate in maintenance mode.Maintenance mode is described in detail above. After reachingequilibrium in maintenance mode in step 3126, and before being acceptedfor transport to the donor site, instrumented lungs 404 are assessed instep 3128. The OCS user may select continuous assessment and/orsequential assessment, both of which have been described above.

Based on the results of the assessment conducted in step 3128, and onother monitored parameters of lungs 404, in some instances, it isdesirable to provide therapy and recruitment to lungs 404 (step 3130).The pathology that occurs most frequently in donor lungs is collapse, oratelectasis. Use of OCS 1000 provides a number of methods of atelectasismanagement. First, lungs 404 may be re-inflated using sigh breathing,i.e., by causing lungs 404 to take breaths of varying tidal volume. Forexample, in one technique, lungs 404 are caused to inhale a first breathhaving a tidal volume of up to about 1000 ml., followed by two or moresmaller breaths having tidal volumes as low as about 100 ml. A secondmethod involves adjusting PEEP levels between values ranging from about2 cm. H₂O to 15 cm. H₂O. In a third method, over-inflated regions oflungs 404 are restrained with the polyurethane wrap that is used toprovide support for lungs 404 when placed on support surface 2810. Suchrestraint allows the judicious application of gas loop pressure tore-inflate collapsed regions of the lungs. In a fourth recruitmentapproach, the I:E ratio is manipulated, which allows the amount of timespent at pressure plateau 658 (FIG. 6) to be increased, helping lungreinflation, without exceeding peak pressure 656 and PEEP levels 652.Fifth, simple manipulation of lungs 404 on support surface 2810 tochange lung position can be an effective recruitment method. Sixth, lungsecretions, and alveoli debris in the trachea are removed by suctionusing a bronchoscope. The bronchoscope is inserted into lungs 404 via aport in a connector between tracheal cannula 700 and gas circuit tubingof lung perfusion module 400. Seventh, surfactant inhalation therapy isperformed by injecting surfactants, preferable in aerosol form, into thegas line during the inhalation phase of a breathing cycle.

Another pathology that is often found in donor lungs is localized edema,which can occur in a single or in multiple lobes. Edema can be remediedon OCS 1000 by manipulating PEEP levels, increasing oncotic pressure byultrafiltration, and manipulation of perfusion fluid pressure by meansof vasodilators and/or the flow rate of pump 226.

Pneumonia is also another common pathology of donor lungs, and can beaddressed by direct injection of anti-microbial agents into perfusionfluid 250, and/or by inhalation of the agents through the ventilatorsystem of lung perfusion module 400. Another pneumonia recruitmenttechnique is broncho-alveolar lavage.

Bronchospasm, which occurs less frequently than the pathologiesdiscussed above, is managed on OCS 1000 with inhaled broncholdilators. Abronchoscope is optionally used to help inject the bronchodilators intothe lungs' airways. Another pathology is high PAP; this is managed byadding vasolidators to perfusion fluid 250.

In some instances, an operator may perform surgery on lungs 404 orprovide therapeutic or other treatment, such as immunosuppressivetreatments, chemotherapy, genetic testing or irradiation therapy.

In general, lungs 404 are placed in maintenance mode while recruitmentis being performed. Assessment step 3128 and recruitment step 3130 maybe repeated several times, and may last for a period of up to severalhours if needed. The goal is to obtain an assessment of lungs 404 thatindicates that the lungs are sufficiently healthy in order to beaccepted for transport to the recipient site. Once this condition issatisfied, OCS 1000, with its instrumented lung 404, is loaded into avehicle for transport to the recipient site.

FIG. 32 illustrates an exemplary usage mode of OCS 1000 during transportfrom the donor site to the recipient site. Before being placed in thetransport vehicle, OCS 1000 is placed into maintenance mode (step 3202).OCS 1000 is then placed in the vehicle and the journey is commenced(step 3204). After a time interval, the lungs are assessed (step 3206).The time interval before the first assessment depends on the conditionof lungs 404 as determined at the donor site, on monitored parameters oflungs 404, and on the anticipated duration of the trip. In general, thepoorer the condition of lungs 404, the sooner an assessment will beconducted. If assessment 3206 finds that lungs 404 are in poorcondition, therapy and recruitment are performed (step 3210). After aperiod of recruitment, another assessment (step 3206) is performed. Thecycle of assessment and recruitment continues until assessment step 3206indicates that lungs 404 are above a certain health threshold, and thenlungs 404 are returned to maintenance mode 3208. In some embodiments, nofurther assessment or recruitment takes place during transport. In otherembodiments, additional assessment and, if necessary, recruitment stepsare performed at intervals during transport. The decision as to whetherto conduct further assessments is governed by the operator's overallassessment of the health of lungs 404, as well as by the availability ofassessment gas in OCS 1000. Arrival at the recipient site (step 3212)completes the journey.

The choice of which form of assessment to perform is determined by bothclinical and technical considerations. From a clinical perspective,perfusion fluid 250 saturation levels are closer to physiologic bloodsaturation levels in continuous assessment than in sequentialassessment. On the other hand, perfusion fluid flow rates are only aboutone third of the physiologic level in continuous assessment, and areclose to physiologic levels in sequential assessment. From a technicalperspective, the choice of assessment method may be constrained by theamount of gas available in the OCS. During transport of lungs 404 fromthe donor site to the recipient site, OCS 1000 functions in aself-contained manner. In particular, it relies on its own internalsupplies of maintenance gas and deoxygenation gas. In an illustrativeconfiguration, OCS 1000 has a 200 liter supply of deoxygenation gas 500.In order to perform a single sequential assessment of the lung,approximately 40 liters of deoxygenation gas is required. However, if alung is in poor health, with a compromised gas exchange capability, morethan 40 liters of deoxygenation gas is required for a sequentialassessment, since it will take a longer time for the perfusate oxygenlevels to fall to the target levels in the deoxygenation phase. Thus,the deoxygenation tank capacity limits the number of sequentialassessments in a trip to a maximum of five, and more generally, four orfewer, depending on the condition of lungs 404. On the other hand,performing continuous assessment does not require the achievement of anytarget deoxygenation level in perfusion fluid 250. Instead, theassessment is run for a fixed time interval, during which deoxygenationgas 500 is flowed through gas exchanger 402 at an average rate of about10 liters/minute. In an illustrative example, continuous assessment isrun for 2 minutes, consuming a total of about 20 liters of deoxygenationgas 500, i.e., about half that consumed in a sequential assessment.Thus, from a technical standpoint, continuous assessment may bepreferable to sequential assessment. In a given trip, OCS 1000 hasenough gas to permit a maximum of five sequential assessments or tencontinuous assessments, or a combination according to the followingequation: 40s+20c=200, where s is the number of sequential assessmentsand c is the number of continuous assessments.

In order to obtain an accurate reading of the perfusate oxygen levels,the perfusate column measured by pulse oxymeters 116 and 118 should befree of gas bubbles. As described above, the dual drain system 2804 and2806 and the perfusate pool above drain 2804 helps ensure that bubblesdo not enter the perfusate line. However, motion of the vehicletransporting OCS 1000 may cause enough agitation to cause some bubblesto drain into the perfusate column. Therefore, in the describedembodiment, the vehicle is parked in a level area while assessment isbeing performed. In other embodiments, lung chamber 2204, lung housing2802 and the dual drain system are modified to make the system moreresistant to motion, such as by confining the blood pool more securely,or by draining perfusate directly into tubes. Such modifications maypermit accurate lungs assessments to be performed even while thetransporting vehicle is moving.

FIG. 33 provides an exemplary process for conducting additional tests onthe lungs 404 while OCS 1000 is at the recipient site. OCS 1000 performsanother assessment (step 3302) of lungs 404. An additional supply ofdeoxygenation gas may be available at the recipient site, which cansupplement the OCS's supply of deoxygenation gas 500 that may have beendepleted during transit from the donor site. If the condition of lungs404 is poor, therapy and recruitment (step 3304) is performed. If, aftera final assessment step, lungs 404 are assessed to be in a conditionsuitable for transplant, lungs 404 are prepared for implantation intothe recipient. This includes configuring OCS 1000 for lung removal bypausing the pump 226 to stop the flow of perfusion fluid 250 (step 3306)and, optionally, administering a pneumoplegia solution to lungs 404.Next, in step 3308, lungs 404 are de-cannulated and removed from thelung chamber assembly 2204. In step 3310, lungs 404 are transplantedinto the recipient patient by inserting them into the recipient's chestcavity and suturing the various pulmonary connections to theirappropriate mating connections within the recipient. In certainembodiments, a portion of the recipient's left atrium may be excised andreplaced with one or more of the donor's left atrial cuff to which thedonor's pulmonary veins are attached. In other embodiments, only one oftwo lungs is removed while the remaining lung continues to be perfusedand ventilated on the OCS.

It is to be understood that while the invention has been described inconjunction with the various illustrative embodiments, the forgoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Forexample, a variety of systems and/or methods may be implemented based onthe disclosure and still fall within the scope of the invention. Otheraspects, advantages, and modifications are within the scope of thefollowing claims. All references cited herein are incorporated byreference in their entirety and made part of this application.

What is claimed is:
 1. A system for preserving a lung ex vivocomprising: a perfusion fluid circuit for circulating a perfusion fluidthrough the lung, the fluid entering the lung through a pulmonary arteryinterface and leaving the lung through a left atrial interface; aventilation circuit for ventilating the lung through a trachealinterface, the ventilation circuit adapted to flow a captive volume of aventilation gas back and forth between the lung and a variable volumechamber; a trickle valve in fluid communication with the ventilationcircuit for introducing into the captive volume an additional volume ofthe ventilation gas; and a relief valve in fluid communication with theventilation circuit for venting excess ventilation gas from the captivevolume and for maintaining a minimum gas pressure of the captive volume;and wherein a gas exchange in the lung between a component of theventilation gas and the perfusion fluid causes the corresponding gascomponent in the perfusion fluid to reach an equilibrium value.
 2. Asystem for preserving a lung ex vivo comprising: means for circulating aperfusion fluid through the lung, the fluid entering the lung through apulmonary artery interface and leaving the lung through a left atrialinterface; means for ventilating the lung through a tracheal interface,a ventilation circuit adapted to flow a captive volume of a ventilationgas back and forth between the lung and a variable volume chamber; meansfor introducing into the captive volume an additional volume of theventilation gas; and means for venting excess ventilation gas from thecaptive volume and for maintaining a minimum gas pressure of the captivevolume, wherein a gas exchange in the lung between a component of theventilation gas and the perfusion fluid causes the corresponding gascomponent in the perfusion fluid to reach an equilibrium value.
 3. Asystem for preserving a lung ex vivo comprising: A pulmonary arteryinterface and a left atrial interface for circulating a perfusion fluidthrough the lung, wherein the fluid enters the lung through thepulmonary artery interface and leaves the lung through the left atrialinterface; a tracheal interface for ventilating the lung; a ventilationcircuit adapted to flow a captive volume of a ventilation gas back andforth between the lung and a variable volume chamber; a first valve forintroducing into the captive volume an additional volume of theventilation gas; and a second valve for venting excess ventilation gasfrom the captive volume and for maintaining a minimum gas pressure ofthe captive volume, wherein a gas exchange in the lung between acomponent of the ventilation gas and the perfusion fluid causes thecorresponding gas component in the perfusion fluid to reach anequilibrium value.
 4. The system of claim 1, wherein the trickle valveis a one-way gas flow valve that only permits flow of a specific volumeof gas into the system.
 5. The system of claim 1, wherein the tricklevalve permits continuous replacement of oxygen consumed by the lungs bypermitting entry of ventilation gas into the system during eachventilation cycle.
 6. The system of claim 1, wherein the relief valveincludes a diaphragm; and wherein the relief valve is controlled byapplying a positive pressure to the diaphragm such that the relief valveremains open, and gas is vented to the outside, as long as the pressurein the ventilation circuit is greater than the pressure on thediaphragm.
 7. The system of claim 3, wherein the pulmonary arteryinterface includes a pulmonary artery cannula, and wherein a portion ofthe pulmonary artery cannula is sized for being inserted into apulmonary artery of the lung.
 8. The system of claim 3, wherein the leftatrial interface includes a sealed connection between a left atrium ofthe lung and a left atrial cannula.
 9. The system of claim 3, whereinthe tracheal interface includes a tracheal cannula, and wherein aportion of the tracheal cannula is sized for being inserted into atrachea of the lung.
 10. The system of claim 1, wherein the trachealinterface includes a conduit by which air is introduced into the lung.11. The system of claim 2, wherein the tracheal interface includes aconduit by which air is introduced into the lung.
 12. The system ofclaim 3, wherein the tracheal interface includes a conduit by which airis introduced into the lung.